RAD18 – Overview and Key Functions OpenAI o3-deep-research-2025-06-26 125 citations 2025-12-27T17:50:44.337046

RAD18 – Overview and Key Functions

RAD18 is a human gene encoding an E3 ubiquitin-protein ligase critical for DNA damage tolerance and repair. The RAD18 protein (UniProt Q9NS91) contains a RING-finger domain that confers E3 ligase activity, a SAP domain for DNA binding, and a ubiquitin-binding zinc-finger (UBZ) domain (www.nature.com) (pmc.ncbi.nlm.nih.gov). These domains enable RAD18 to recognize stalled DNA replication sites and coordinate the post-replication repair (PRR) pathway. RAD18 is conserved from yeast to humans and interacts with the E2 ubiquitin-conjugating enzyme RAD6 (also known as UBE2A/B in humans) (www.ncbi.nlm.nih.gov). Together, the RAD18–RAD6 complex monoubiquitinates proliferating cell nuclear antigen (PCNA) on Lysine-164 of PCNA (www.nature.com). PCNA is a DNA-sliding clamp and a master coordinator of replication and repair proteins at replication forks (pmc.ncbi.nlm.nih.gov). By tagging PCNA with ubiquitin, RAD18 acts as a molecular switch that prevents replication fork collapse, allowing cells to tolerate DNA damage during S phase (pmc.ncbi.nlm.nih.gov). This post-replication “damage tolerance” mechanism is distinct from direct DNA repair: rather than immediately fixing a DNA lesion, RAD18-mediated PCNA ubiquitination permits DNA synthesis to continue past the lesion, avoiding deadly fork stalling (pmc.ncbi.nlm.nih.gov).

Role in DNA Damage Tolerance – Translesion Synthesis and Template Switching

Translesion DNA Synthesis (TLS): The primary function of RAD18 is to trigger TLS, a process by which specialized DNA polymerases replicate across damaged DNA templates. Upon DNA damage (e.g. UV-induced lesions), RAD18-RAD6 adds a single ubiquitin to PCNA (monoubiquitination), which creates a docking signal for Y-family TLS polymerases such as Polη (eta) and Polκ (kappa) (www.nature.com) (www.nature.com). These polymerases have low-fidelity but can accommodate distorted DNA bases, allowing replication to bypass lesions (www.nature.com). TLS is error-prone, often introducing mutations, but it is vital for avoiding acute replication failure. For example, cells lacking RAD18 cannot ubiquitinate PCNA after UV damage and fail to recruit Polη, leading to stalled replication and hypersensitivity to UV (www.ncbi.nlm.nih.gov) (www.nature.com). A landmark study in yeast first linked RAD6–RAD18 to PCNA ubiquitination as the key step in DNA damage tolerance (pmc.ncbi.nlm.nih.gov), a finding later confirmed in human cells (www.nature.com). In human fibroblasts, RAD18 knockouts display defective replication on UV-damaged templates and increased chromosomal breaks, underscoring RAD18’s role in maintaining fork progression (www.ncbi.nlm.nih.gov). Consistently, RAD18-deficient mouse cells show elevated genomic instability and mutagen sensitivity (pmc.ncbi.nlm.nih.gov).

Template Switching (Error-Free PRR): In addition to TLS, RAD18-initiated PCNA ubiquitination can be channeled into an error-free damage bypass pathway. Monoubiquitin on PCNA can be extended into a Lys-63–linked polyubiquitin chain by other E3 ligases (in yeast, Rad5; in human, HLTF and SHPRH) (www.nature.com). This polyubiquitinated PCNA promotes a template switching mechanism, where the replication machinery bypasses the lesion by using the newly synthesized sister chromatid as a template instead of the damaged strand. Template switching avoids mutations and complements the TLS pathway. RAD18 is required for this process as the initiator of PCNA ubiquitination, even though the extension to polyubiquitin involves additional factors (www.nature.com). Through TLS and template switching, RAD18 safeguards replication: it allows cells to tolerate DNA lesions during S phase, deferring repair to after replication. A 2024 report in Nucleic Acids Research succinctly stated that RAD18 “prevents replication fork collapse by promoting DNA translesion synthesis and template switching,” highlighting its dual role in these tolerance pathways (pmc.ncbi.nlm.nih.gov).

Molecular Mechanism and Interactions

PCNA Ubiquitination Reaction: RAD18 functions as a RING-type E3 ligase that works with the E2 enzyme RAD6. RAD18 directly binds RAD6 via a conserved RING/Rad6-binding domain and facilitates transfer of ubiquitin from RAD6 to PCNA (pubmed.ncbi.nlm.nih.gov). Notably, human RAD18 specifically ubiquitinates PCNA at K164, and this modification is absolutely dependent on RAD18-RAD6 in vivo (www.nature.com). In biochemical assays, the RAD18/RAD6 complex predominantly catalyzes monoubiquitination rather than polyubiquitin chain formation (pubmed.ncbi.nlm.nih.gov). Structural studies indicate RAD18 likely forms a homo-dimer and encircles DNA together with PCNA and RAD6, ensuring ubiquitin is attached to PCNA’s DNA-bound form (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). RAD18 contains a SAP domain (a DNA-binding motif) that preferentially binds single-stranded DNA, helping target the ligase to stalled replication forks where stretches of single-stranded DNA accumulate (pmc.ncbi.nlm.nih.gov). This targeting is enhanced by RAD18’s UBZ domain, which can bind ubiquitin — a recent study showed RAD18’s UBZ domain recognizes ubiquitinated chromatin marks at damage sites (pmc.ncbi.nlm.nih.gov). Indeed, recruitment of RAD18 to sites of stalled replication involves RPA-coated ssDNA and possibly pre-existing ubiquitinated proteins. For example, both ATR kinase activation and RAD18 loading are triggered by RPA-ssDNA, suggesting RAD18 scans replication protein A filaments for fork distress signals (www.embopress.org). Once localized, RAD18 ubiquitinates PCNA, which in turn attracts TLS polymerases that also carry ubiquitin-binding motifs (UBM/UBZ in Polη, Polκ) (www.nature.com).

Key Interactions: Beyond PCNA and RAD6, RAD18 interacts with multiple genome maintenance proteins. It physically associates with REV1/Polη in cells to facilitate polymerase switch during TLS (www.nature.com). Intriguingly, RAD18 also binds the recombination factor RAD51C, a paralog of RAD51, and helps localize RAD51C to DNA breaks (www.nature.com) (www.nature.com). This suggests RAD18 serves as a hub connecting replication stress tolerance to homologous recombination (HR) repair. Regulatory proteins modulate RAD18’s activity via binding: for instance, the MAGEA4 oncoprotein (a cancer-testis antigen) binds directly to RAD18’s C-terminal domain. A 2024 EMBO Journal study reported that MAGEA4 docking on RAD18 partially displaces RAD6 and inhibits RAD18’s auto-ubiquitination, thereby stabilizing the RAD18 protein (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Normally, RAD18 can undergo autoubiquitination (tags itself for degradation to turn off its signal), but MAGEA4 binding protects RAD18 from self-degradation (pmc.ncbi.nlm.nih.gov). This interaction enhances RAD18’s TLS activity and is thought to encourage error-prone DNA synthesis in cancer cells overexpressing MAGEA4 (pmc.ncbi.nlm.nih.gov). In healthy tissue, RAD18 and MAGEA4 are both highly expressed in testes and during spermatogenesis (pmc.ncbi.nlm.nih.gov), hinting that this regulatory mechanism may operate in germ cells. Aberrant MAGEA4 expression in tumors effectively “hijacks” RAD18, keeping it active even without exogenous DNA damage, which can exacerbate genomic instability (pmc.ncbi.nlm.nih.gov). The RAD18–MAGEA4 interface is now being explored as a potential drug target to block TLS in cancers (pmc.ncbi.nlm.nih.gov).

Subcellular Localization and Regulation

Localization: Consistent with its role in DNA replication and repair, RAD18 is predominantly a nuclear protein. Immunohistochemistry data show RAD18 has selective nuclear expression in proliferating cell types – for example, in germinal center B-cells and spermatogonia in testis, RAD18 is strongly nuclear (www.proteinatlas.org). In cell culture, RAD18 relocalizes to nuclear foci upon DNA damage. These foci often colocalize with replication fork markers such as PCNA. A study of gastric cancer tissues confirmed that RAD18 protein is mainly detected in the nucleus of tumor cells (pubmed.ncbi.nlm.nih.gov). RAD18 does not have a classic nuclear localization sequence, but its binding partners (PCNA, RPA, etc.) and DNA-binding SAP domain concentrate it in the nucleus. Notably, RAD18 can shuttle to sites of double-strand breaks and stalled forks as needed. For example, after UV irradiation or replication stress, RAD18 accumulates at damage sites in an RPA- and PCNA-dependent manner (www.embopress.org). RAD18’s PIP motif (PCNA-interacting peptide) near its C-terminus also contributes to binding PCNA directly (www.embopress.org). Recent research (EMBO J, 2024) identified that the ATR kinase phosphorylates RAD18 at Ser403, adjacent to this PIP motif, which weakens RAD18’s interaction with PCNA (www.embopress.org). This phosphorylation by ATR is a key regulatory mechanism to restrict RAD18 activity during replication stress (www.embopress.org). By limiting how tightly RAD18 binds PCNA, ATR prevents excessive PCNA ubiquitination. This is physiologically important, as unchecked RAD18 activity can lead to aberrant processing of replication forks (discussed below). In summary, RAD18 is constitutively nuclear in cycling cells and dynamically enriched at DNA lesions, with its localization and activity finely tuned by cell-cycle checkpoints.

Post-translational Regulation: Cells tightly regulate RAD18 through modifications to ensure it acts at the right time and place. ATR-mediated phosphorylation is one such control: upon replication stress, ATR phosphorylates RAD18 (Ser403), causing RAD18 to release PCNA and thus limiting PCNA monoubiquitination (www.embopress.org). Functionally, this prevents an overactivation of the TLS pathway. A 2024 study demonstrated that inhibiting ATR led to excessive RAD18-dependent PCNA ubiquitination and consequent replication fork breakage – an outcome that could be rescued by RAD18 knockdown or a PCNA-K164R (non-ubiquitinable) mutant (www.embopress.org) (www.embopress.org). Thus, ATR acts as a brake on RAD18 to preserve replication fork stability (www.embopress.org) (www.embopress.org). Another layer of regulation is O-GlcNAcylation (O-linked N-acetylglucosamine modification) of RAD18. Emerging evidence (Cell Death & Disease, 2024) indicates RAD18 is modified by O-GlcNAc at multiple residues (Ser130, Ser164, Thr468), mediated by the OGT enzyme that localizes to DNA damage sites (www.nature.com) (www.nature.com). Loss of RAD18’s O-GlcNAc modification (by mutating those sites) impairs its recruitment to damaged DNA and reduces its ability to ubiquitinate PCNA (www.nature.com). Mechanistically, O-GlcNAcylation of RAD18 was required for efficient RAD18 phosphorylation at Ser434 by CDC7 kinase, which in turn promotes PCNA ubiquitination and Polη focus formation (www.nature.com). Cells expressing an O-GlcNAc-deficient RAD18 mutant showed reduced HR repair and heightened sensitivity to DNA damage (www.nature.com). Therefore, O-GlcNAcylation positively regulates RAD18, enhancing both TLS and homologous recombination functions. RAD18 is also subject to autoubiquitination, as mentioned earlier. Autoubiquitination typically targets RAD18 for proteasomal degradation, serving as a negative feedback to turn off PRR once lesions are bypassed (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Interactions with proteins like MAGEA4 that suppress autoubiquitination will prolong RAD18’s half-life. In summary, phosphorylation (ATR), glycosylation (O-GlcNAc), and self-ubiquitination of RAD18 all integrate to modulate the timing and intensity of RAD18’s activity in the DNA damage response.

Biological Processes and Pathways Involving RAD18

Post-Replication Repair (PRR) Pathway: RAD18 is a central player in the PRR pathway, also known as the DNA damage tolerance pathway. This pathway comes into play when replication forks encounter DNA lesions that cannot be immediately repaired. Rather than stalling indefinitely, PRR allows forks to bypass lesions, and repair is handled after DNA replication. RAD18’s ubiquitination of PCNA is the molecular trigger for PRR (pmc.ncbi.nlm.nih.gov). Depending on context, RAD18-mediated PCNA ubiquitination can initiate error-prone TLS or be coupled to error-free template switching. The importance of RAD18 in PRR is illustrated by the Rad18 knockout phenotype: RAD18-null mouse embryonic stem cells and knockout mice exhibit defective post-replication repair, evidenced by accumulation of daughter-strand gaps behind replication forks and elevated sensitivity to UV, methylating agents, and other mutagens (pmc.ncbi.nlm.nih.gov). In S. cerevisiae, rad18 mutants were first discovered for their inability to survive DNA damage despite intact excision repair, defining the post-replication repair pathway. Human RAD18 restores post-replication repair when expressed in rad18-deficient yeast (pmc.ncbi.nlm.nih.gov), highlighting the pathway’s conservation. RAD18 also interacts with the Fanconi Anemia (FA) pathway, which is another post-replication repair mechanism especially for DNA interstrand crosslinks. A recent study (PLoS Genetics, 2022) found that RAD18 helps recruit the Fanconi anemia protein FANCD2 to sites of transcription-replication conflicts (pmc.ncbi.nlm.nih.gov). In RAD18-deficient human cells, R-loop structures (RNA–DNA hybrids) accumulate, leading to replication stress and double-strand breaks, partly because FANCD2 fails to localize to resolve these R-loops (pmc.ncbi.nlm.nih.gov). RAD18 activity was shown to be critical for activating FANCD2 under replication stress caused by either transcription blockage or mild replication inhibitors (pmc.ncbi.nlm.nih.gov). Thus, RAD18 links standard PRR (PCNA ubiquitination) with the FA pathway to protect stalled forks from transcriptional interference. This underscores a broader role for RAD18: it’s not only guarding against exogenous DNA damage like UV, but also against endogenous stresses such as hard-to-replicate sequences and R-loops (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Homologous Recombination (HR) and Double-Strand Break Repair: Although traditionally associated with replication lesions, RAD18 has emerging roles in double-strand break (DSB) repair, particularly in promoting HR. In the context of a one-ended DSB arising at a collapsed replication fork, RAD18 appears to channel repair toward HR (error-free repair using a sister chromatid) rather than non-homologous end joining (NHEJ). In mid-2024, Palek et al. reported that RAD18 is actively recruited to DSBs in post-replicative chromatin by recognizing ubiquitylated histone H2A marks (pmc.ncbi.nlm.nih.gov). Specifically, ubiquitination of histone H2A at K15 (placed by upstream DNA damage response E3s like RNF168) creates a binding site for RAD18’s UBZ domain (pmc.ncbi.nlm.nih.gov). RAD18’s presence at breaks then antagonizes 53BP1 loading (pmc.ncbi.nlm.nih.gov). 53BP1 is a factor that favors NHEJ and blocks DNA end resection; by limiting 53BP1 accumulation, RAD18 tilts the balance toward resection and homologous recombination. Using super-resolution microscopy, RAD18 was seen localizing adjacent to DSB sites and confining 53BP1 to peripheral chromatin domains around the break (pmc.ncbi.nlm.nih.gov). Mechanistically, RAD18’s effect required cooperation with SLF1 (SCAF-like factor 1), which helps target RAD18 to newly replicated chromatin marked by unmethylated H4K20 (H4K20me0 is a signature of post-replicative chromatin) (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). Intriguingly, RAD18’s own ubiquitin ligase activity is auto-regulated at DSBs: if RAD18 autoubiquitinates itself (with RAD6’s help), its recruitment to breaks is inhibited (pmc.ncbi.nlm.nih.gov). By preventing self-ubiquitination (for example, via SLF1 or MAGEA4 as discussed), RAD18 can persist at damage sites and promote HR repair. Supporting this model, mutations in RAD18 found in some cancer patients impaired RAD18’s recruitment to DSBs and were associated with genomic instability (www.sciencedirect.com) (pubmed.ncbi.nlm.nih.gov). In summary, RAD18 extends its influence beyond replication forks to the realm of DSB repair: it helps decide the repair pathway choice by favoring homologous recombination in replicating cells, thereby preventing toxic misrepair.

Replication Stress and Fork Rescue: Oncogene activation and other intrinsic stressors often cause replication fork stalling or slowing, known as replication stress. RAD18 has been identified as a key factor that cancer cells exploit to survive high levels of replication stress. A notable study (J. Cell Biol., 2017) showed that RAD18 and Polκ enable tolerance of oncogene-induced replication stress, such as that caused by Cyclin E overexpression (pmc.ncbi.nlm.nih.gov). RAD18-deficient cells fail to resolve stalled forks efficiently and undergo lethal fork collapse when driven into unscheduled replication by oncogenic signals (pmc.ncbi.nlm.nih.gov). In line with this, cells require RAD18 to recover from prolonged S-phase checkpoint arrest (pmc.ncbi.nlm.nih.gov). Recent evidence also points to RAD18’s role in alternative replication rescue pathways like break-induced replication (BIR) (pmc.ncbi.nlm.nih.gov), a process to restart broken forks. These diverse functions position RAD18 as a central responder to replication impediments, whether they are DNA lesions, difficult-to-replicate DNA structures, or collisions between replication and transcription machineries (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). By catalyzing PCNA ubiquitination and cooperating with multiple repair pathways, RAD18 coordinates a network of responses that preserve genome integrity during DNA synthesis.

RAD18 in Health and Disease

Cancer Genomics and Mutagenesis: Given its role in tolerating DNA damage (often at the cost of introducing mutations), RAD18 has a complex relationship with cancer. On one hand, RAD18 is protective against acute DNA damage and genomic instability; on the other, its error-prone bypass of lesions can contribute to mutagenesis. High levels of RAD18 have been observed in many cancers, and this is often associated with aggressive disease. For instance, a 2020 clinical study of 96 gastric cancer patients found that tumors with strong RAD18 expression had significantly higher rates of lymph node metastasis and vascular invasion, and patients with RAD18-high tumors had markedly shorter overall survival (pubmed.ncbi.nlm.nih.gov). Specifically, high nuclear RAD18 in gastric tumors correlated with advanced stage (p = 0.0253) and poor prognosis (p = 0.0061 for overall survival) (pubmed.ncbi.nlm.nih.gov). Similarly, in triple-negative breast cancer (TNBC), RAD18 was shown to be overexpressed in high-grade tumors and to correlate inversely with patient survival (pmc.ncbi.nlm.nih.gov). Experimental models have elucidated how RAD18 may drive cancer progression: RAD18’s TLS activity can generate mutations that fuel tumor evolution (pmc.ncbi.nlm.nih.gov). In TNBC cells, RAD18 was found to promote a cancer stem cell-like phenotype via interaction with the Hippo/YAP signaling pathway (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). RAD18 also engages in a positive feedback loop with tumor-associated macrophages: tumor-secreted factors induce macrophages to produce TGF-β, which in turn activates RAD18 and YAP in cancer cells, sustaining stemness and therapy resistance (pmc.ncbi.nlm.nih.gov). These findings underscore that RAD18 is not simply a repair protein but can be co-opted by tumors to enhance malignant traits (metastasis, stemness, mutational adaptability).

Therapeutic Resistance: Cancer cells often rely on RAD18 to survive DNA-damaging treatments, making it a factor in chemo- and radio-resistance. Overexpression of RAD18 has been linked to resistance to platinum chemotherapy in colorectal cancer and to radiotherapy in glioblastoma and lung cancers (www.nature.com) (www.nature.com). For example, knocking down RAD18 in glioma models increased their sensitivity to ionizing radiation, indicating RAD18 normally helps repair or tolerate radiation-induced DNA damage (www.nature.com). Mechanistically, RAD18 can modulate the repair of therapy-induced DNA lesions: one study showed RAD18 overexpression in esophageal carcinoma enhanced repair of radiation damage by regulating DNA-PKcs (a key NHEJ factor) (pmc.ncbi.nlm.nih.gov). Another report described RAD18 promoting epithelial–mesenchymal transition (EMT) and metastasis in colorectal cancer, suggesting RAD18’s activity may extend to altering gene expression programs via DNA damage signals (pmc.ncbi.nlm.nih.gov). These insights have motivated efforts to target RAD18 or its partners pharmacologically. Small-molecule inhibitors of the RAD18 pathway are being explored as adjuvants to cancer therapy. In 2022, researchers discovered a series of xanthene compounds (e.g., “TZ9”) that disrupt RAD6–RAD18 function, thereby blocking PCNA ubiquitination (pmc.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). These compounds inhibit the RAD6~Ub thioester formation and the RAD6–RAD18 interaction, effectively shutting down TLS (pmc.ncbi.nlm.nih.gov). Notably, treating cells with a RAD6/RAD18 inhibitor (like TZ9) phenocopies RAD18 loss: it prevented NiV virus protein ubiquitination (as discussed below) and also impaired post-replication repair (pubmed.ncbi.nlm.nih.gov). Patent literature in 2021–2023 reflects active interest in RAD18 inhibitors for cancer treatment, indicating preclinical development of molecules aiming to block RAD18-mediated tolerance in tumors (patents.google.com) (patents.justia.com). The rationale is that disabling RAD18 will render cancer cells less able to cope with therapy-induced DNA damage or replication stress, thereby enhancing the efficacy of chemo/radiation. However, this strategy must balance the potential for increased normal tissue toxicity and genomic instability.

Viral Exploitation of RAD18: In an interesting twist, viruses can hijack the RAD18 pathway for their own life cycle. A recent study (Cell Reports, 2023) on Nipah virus (NiV) – a highly pathogenic paramyxovirus – revealed that NiV usurps the RAD6–RAD18 ubiquitin complex to modify its matrix (M) protein (pubmed.ncbi.nlm.nih.gov). The NiV M protein must shuttle from the nucleus (where virions assemble) to the cytoplasm for viral budding. RAD18 was found to directly ubiquitinate NiV M at Lys258 via K63-linked polyubiquitin chains, using RAD6A as the E2 enzyme (pubmed.ncbi.nlm.nih.gov). This ubiquitination of M is crucial for its nuclear export: ubiquitinated M relocalizes to the cytoplasm and reaches the plasma membrane for virion release (pubmed.ncbi.nlm.nih.gov). Disrupting the RAD18–RAD6A complex, either by mutating RAD18’s RING domain or applying the RAD6 inhibitor TZ9, blocked M’s ubiquitination and trapped the M protein in the nucleus (pubmed.ncbi.nlm.nih.gov). As a result, NiV and the related Hendra virus were unable to efficiently bud from infected cells, greatly attenuating infection (pubmed.ncbi.nlm.nih.gov). This finding identifies RAD18 as a host factor essential for NiV egress. It suggests that RAD18 inhibitors might serve as antivirals against certain viruses, although host DNA repair would concurrently be affected. Nonetheless, the NiV example highlights RAD18’s versatile enzymatic activity – extending beyond PCNA to ubiquitinate other proteins (here a viral protein) when recruited to them. It also provides a “real-world” demonstration that small molecules targeting the RAD18/RAD6 pathway (like TZ9) can have tangible biological effects (e.g. blocking a lethal virus) (pubmed.ncbi.nlm.nih.gov).

Expert Perspectives and Current Research Frontiers

RAD18 is widely regarded by experts as a master regulator of replication stress responses. As an authoritative review noted, RAD18 “coordinates multiple DNA repair and damage tolerance pathways including post-replication repair, homologous recombination, Fanconi anemia, and break-induced replication” (pmc.ncbi.nlm.nih.gov). By modifying the key sliding clamp PCNA, RAD18 orchestrates the switch between high-fidelity replication and specialized rescue pathways (pmc.ncbi.nlm.nih.gov). This central role has made RAD18 a focal point in understanding how cells maintain genome stability. Recent research (2022–2024) has significantly expanded our understanding of RAD18’s functions:
- Transcription-Associated Damage: Wells et al. (PLoS Genet, Dec 2022) demonstrated that RAD18 prevents transcription-replication conflicts from turning into DNA breaks by recruiting FANCD2 to resolve R-loops (pmc.ncbi.nlm.nih.gov). This indicates RAD18 is active at common fragile sites and conflict-prone genes, not just at exogenous damage sites.
- DSB Repair Choice: Palek et al. (Nucleic Acids Res, July 2024) showed RAD18 is a novel factor in DSB repair pathway choice – promoting HR by excluding 53BP1 in the context of newly replicated chromatin (pmc.ncbi.nlm.nih.gov). This was a surprising new role, hinting that RAD18 links the replication-coupled repair of one-ended breaks to the classical HR machinery.
- Regulatory Modifications: Zhang et al. (Cell Death Dis., 2024) uncovered the O-GlcNAc modification of RAD18 as a key enhancer of its activity in both TLS and HR, connecting cellular metabolic status (glucose levels) to DNA repair capacity (www.nature.com) (www.nature.com). In parallel, Okano et al. (EMBO J., 2024) identified ATR kinase as a checkpoint that restrains RAD18, thereby protecting replication forks and telomeres from excessive processing (www.embopress.org) (www.embopress.org). This kind of crosstalk between checkpoint signaling and RAD18 ensures a balance between damage bypass and fork stability.
- Structural Insights: Griffith-Jones et al. (EMBO J., 2024) provided high-resolution insight into RAD18’s regulation by cancer-testis antigens (MAGE proteins). Their work solved how MAGEA4 binds RAD18’s RING domain and RAD6-binding domain, stabilizing the ligase and enhancing its activity (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This not only explained one mechanism of chemoresistance in MAGEA4-positive tumors, but also suggested a new therapeutic angle: disrupting the RAD18–MAGEA4 interaction may selectively sensitize cancer cells (pmc.ncbi.nlm.nih.gov).
- Disease Models: Recent in vivo studies have examined RAD18 in disease contexts. For example, a 2024 Scientific Reports study tested RAD18’s role in B cell lymphomas using Rad18-knockout mice. Spontaneously, Rad18-deficient mice had increased B-cell malignancies after carcinogen exposure (www.nature.com), but in an aggressive Myc-driven lymphoma model, loss of Rad18 did not significantly alter tumor onset (www.nature.com) (www.nature.com). These results imply that RAD18’s role in cancer can be context-dependent and potentially compensated by parallel pathways in some cell types (www.nature.com).

Overall, current expert consensus portrays RAD18 as a guardian of replication that, if dysregulated, can become a double-edged sword – preventing catastrophic genome damage on one hand, but enabling genome instability and therapy resistance on the other (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Its importance is underscored by the breadth of processes it touches: from ensuring fertility (spermatogenesis requires RAD18 for meiotic DNA repair (www.nature.com)) to influencing the outcomes of cancer therapy. As of 2024, RAD18 remains an active research focus. Key open questions include how RAD18 selects its substrates (beyond PCNA and the few known targets), how it is coordinated with polymerase choice in different lesions, and whether transient RAD18 inhibition can be a safe and effective strategy to augment cancer treatments. Ongoing clinical interest is evident – RAD18 expression is being evaluated as a prognostic biomarker, and preclinical trials of RAD18-pathway inhibitors are likely on the horizon (patents.google.com) (patents.justia.com).

In summary, RAD18 is a pivotal E3 ligase in human cells with a well-established role in monoubiquitinating PCNA to promote DNA damage tolerance. It operates at the crossroads of DNA replication, repair, and checkpoint signaling, ensuring that cells can bypass DNA lesions and recover from replication stress. Cutting-edge studies in 2023–2024 have expanded its known functions to include aiding homologous recombination and preventing transcription-associated genome instability, as well as illuminating mechanisms of its regulation. Clinically, while essential for genome stability, RAD18’s activity can be a liability when hijacked by cancer cells or viruses – making it an attractive, if challenging, target for therapeutic intervention. As one research group aptly summarized, “RAD18 plays numerous roles in genome instability, driven mostly through regulated ubiquitination of [its] primary substrate, PCNA” (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Understanding and modulating those roles continues to be critical in the quest to maintain genomic integrity and improve disease outcomes.

Citations

  1. AnnotationURLCitation(end_index=425, start_index=331, title='RAD18 O-GlcNAcylation promotes translesion DNA synthesis and homologous recombination repair | Cell Death & Disease', type='url_citation', url='https://www.nature.com/articles/s41419-024-06700-y#:~:text=,binding%20zinc')
  2. AnnotationURLCitation(end_index=577, start_index=426, title='Functional characterization of Rad18 domains for Rad6, ubiquitin, DNA binding and PCNA modification - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2034485/#:~:text=Functional%20characterization%20of%20Rad18%20domains,stranded%20DNA')
  3. AnnotationURLCitation(end_index=965, start_index=845, title='RAD18 RAD18 E3 ubiquitin protein ligase [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene/56852#:~:text=The%20protein%20encoded%20by%20this,Expression')
  4. AnnotationURLCitation(end_index=1182, start_index=1088, title='RAD18 O-GlcNAcylation promotes translesion DNA synthesis and homologous recombination repair | Cell Death & Disease', type='url_citation', url='https://www.nature.com/articles/s41419-024-06700-y#:~:text=,binding%20zinc')
  5. AnnotationURLCitation(end_index=1406, start_index=1293, title='RAD18 opposes transcription-associated genome instability through FANCD2 recruitment - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9767342/#:~:text=replication%20%28BIR%29%20,12')
  6. AnnotationURLCitation(end_index=1727, start_index=1571, title='RAD18 directs DNA\xa0double-strand break repair by homologous recombination to post-replicative chromatin - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11260465/#:~:text=RAD18%20is%20an%20E3%20ubiquitin,and%20limits%20the%20distribution%20of')
  7. AnnotationURLCitation(end_index=2133, start_index=1977, title='RAD18 directs DNA\xa0double-strand break repair by homologous recombination to post-replicative chromatin - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11260465/#:~:text=RAD18%20is%20an%20E3%20ubiquitin,and%20limits%20the%20distribution%20of')
  8. AnnotationURLCitation(end_index=2713, start_index=2593, title='RAD18 O-GlcNAcylation promotes translesion DNA synthesis and homologous recombination repair | Cell Death & Disease', type='url_citation', url='https://www.nature.com/articles/s41419-024-06700-y#:~:text=The%20E3%20ubiquitin%20ligase%20RAD18,mUb')
  9. AnnotationURLCitation(end_index=2808, start_index=2714, title='RAD18 O-GlcNAcylation promotes translesion DNA synthesis and homologous recombination repair | Cell Death & Disease', type='url_citation', url='https://www.nature.com/articles/s41419-024-06700-y#:~:text=,binding%20zinc')
  10. AnnotationURLCitation(end_index=3046, start_index=2926, title='RAD18 O-GlcNAcylation promotes translesion DNA synthesis and homologous recombination repair | Cell Death & Disease', type='url_citation', url='https://www.nature.com/articles/s41419-024-06700-y#:~:text=The%20E3%20ubiquitin%20ligase%20RAD18,mUb')
  11. AnnotationURLCitation(end_index=3435, start_index=3315, title='RAD18 RAD18 E3 ubiquitin protein ligase [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene/56852#:~:text=The%20protein%20encoded%20by%20this,Expression')
  12. AnnotationURLCitation(end_index=3567, start_index=3436, title='RAD18 O-GlcNAcylation promotes translesion DNA synthesis and homologous recombination repair | Cell Death & Disease', type='url_citation', url='https://www.nature.com/articles/s41419-024-06700-y#:~:text=damage%20sites,and%20RAD51C%20binding%20ability%20of')
  13. AnnotationURLCitation(end_index=3850, start_index=3682, title='A series of xanthenes inhibiting Rad6 function and Rad6-Rad18 interaction in the PCNA ubiquitination cascade - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8958325/#:~:text=The%20ubiquitination%20of%20PCNA%20on,and%20other%20replication%2C%20repair%2C%20and')
  14. AnnotationURLCitation(end_index=3987, start_index=3893, title='RAD18 O-GlcNAcylation promotes translesion DNA synthesis and homologous recombination repair | Cell Death & Disease', type='url_citation', url='https://www.nature.com/articles/s41419-024-06700-y#:~:text=,binding%20zinc')
  15. AnnotationURLCitation(end_index=4297, start_index=4177, title='RAD18 RAD18 E3 ubiquitin protein ligase [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene/56852#:~:text=The%20protein%20encoded%20by%20this,Expression')
  16. AnnotationURLCitation(end_index=4534, start_index=4399, title='Enhanced Genomic Instability and Defective Postreplication Repair in RAD18 Knockout Mouse Embryonic Stem Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC151530/#:~:text=Enhanced%20Genomic%20Instability%20and%20Defective,2')
  17. AnnotationURLCitation(end_index=4960, start_index=4835, title='Role of Rad18 in B cell activation and lymphomagenesis | Scientific Reports', type='url_citation', url='https://www.nature.com/articles/s41598-024-57018-w#:~:text=PCNA%2C%20mediated%20by%20Rad6%20together,free')
  18. AnnotationURLCitation(end_index=5521, start_index=5396, title='Role of Rad18 in B cell activation and lymphomagenesis | Scientific Reports', type='url_citation', url='https://www.nature.com/articles/s41598-024-57018-w#:~:text=PCNA%2C%20mediated%20by%20Rad6%20together,free')
  19. AnnotationURLCitation(end_index=6070, start_index=5914, title='RAD18 directs DNA\xa0double-strand break repair by homologous recombination to post-replicative chromatin - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11260465/#:~:text=RAD18%20is%20an%20E3%20ubiquitin,and%20limits%20the%20distribution%20of')
  20. AnnotationURLCitation(end_index=6506, start_index=6348, title='The E3 ligase RAD18-mediated ubiquitination of henipavirus matrix protein promotes its nuclear-cytoplasmic trafficking and viral egress - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/39628457/#:~:text=novel%20mechanism%20by%20which%20Nipah,the%20cytoplasm%2C%20directing%20it%20to')
  21. AnnotationURLCitation(end_index=6736, start_index=6642, title='RAD18 O-GlcNAcylation promotes translesion DNA synthesis and homologous recombination repair | Cell Death & Disease', type='url_citation', url='https://www.nature.com/articles/s41419-024-06700-y#:~:text=,binding%20zinc')
  22. AnnotationURLCitation(end_index=7040, start_index=6871, title='E3 ligase Rad18 promotes monoubiquitination rather than ubiquitin chain formation by E2 enzyme Rad6 - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/21422291/#:~:text=E3%20ligase%20Rad18%20promotes%20monoubiquitination,The%20E2%2FE3%20complex%20Rad6%2FRad18')
  23. AnnotationURLCitation(end_index=7390, start_index=7205, title='Asymmetric nature of two subunits of RAD18, a RING-type ubiquitin ligase E3, in the human RAD6A–RAD18 ternary complex - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3273806/#:~:text=E3%2C%20in%20the%20human%20RAD6A%E2%80%93RAD18,human%20RAD6A%E2%80%93RAD18%20ternary%20complex%20Yuji')
  24. AnnotationURLCitation(end_index=7542, start_index=7391, title='Functional characterization of Rad18 domains for Rad6, ubiquitin, DNA binding and PCNA modification - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2034485/#:~:text=Functional%20characterization%20of%20Rad18%20domains,stranded%20DNA')
  25. AnnotationURLCitation(end_index=7901, start_index=7750, title='Functional characterization of Rad18 domains for Rad6, ubiquitin, DNA binding and PCNA modification - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2034485/#:~:text=Functional%20characterization%20of%20Rad18%20domains,stranded%20DNA')
  26. AnnotationURLCitation(end_index=8242, start_index=8078, title='RAD18 directs DNA\xa0double-strand break repair by homologous recombination to post-replicative chromatin - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11260465/#:~:text=classical%20role%2C%20RAD18%20has%20been,and%20limits%20the%20distribution%20of')
  27. AnnotationURLCitation(end_index=8695, start_index=8552, title='ATR limits Rad18-mediated PCNA monoubiquitination to preserve replication fork and telomerase-independent telomere stability | The EMBO Journal', type='url_citation', url='https://www.embopress.org/doi/10.1038/s44318-024-00066-9#:~:text=2005%29,the%20precise%20molecular%20crosstalk%20between')
  28. AnnotationURLCitation(end_index=8963, start_index=8843, title='RAD18 O-GlcNAcylation promotes translesion DNA synthesis and homologous recombination repair | Cell Death & Disease', type='url_citation', url='https://www.nature.com/articles/s41419-024-06700-y#:~:text=The%20E3%20ubiquitin%20ligase%20RAD18,mUb')
  29. AnnotationURLCitation(end_index=9288, start_index=9165, title='Role of Rad18 in B cell activation and lymphomagenesis | Scientific Reports', type='url_citation', url='https://www.nature.com/articles/s41598-024-57018-w#:~:text=match%20at%20L77%20Several%20studies,induced')
  30. AnnotationURLCitation(end_index=9559, start_index=9418, title='RAD18 O-GlcNAcylation promotes translesion DNA synthesis and homologous recombination repair | Cell Death & Disease', type='url_citation', url='https://www.nature.com/articles/s41419-024-06700-y#:~:text=conjugase%20RAD6%20is%20specifically%20required,binding%20zinc')
  31. AnnotationURLCitation(end_index=9704, start_index=9560, title='RAD18 O-GlcNAcylation promotes translesion DNA synthesis and homologous recombination repair | Cell Death & Disease', type='url_citation', url='https://www.nature.com/articles/s41419-024-06700-y#:~:text=RAD18%20at%20DNA%20double,establishing%20a%20new%20rationale%20to')
  32. AnnotationURLCitation(end_index=10315, start_index=10167, title='Structural basis for RAD18 regulation by MAGEA4 and its implications for RING ubiquitin ligase binding by MAGE family proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10987633/#:~:text=,inhibits%20degradative%20RAD18%20autoubiquitination%2C%20which')
  33. AnnotationURLCitation(end_index=10434, start_index=10316, title='Structural basis for RAD18 regulation by MAGEA4 and its implications for RING ubiquitin ligase binding by MAGE family proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10987633/#:~:text=,degradative%20autoubiquitination')
  34. AnnotationURLCitation(end_index=10730, start_index=10593, title='Structural basis for RAD18 regulation by MAGEA4 and its implications for RING ubiquitin ligase binding by MAGE family proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10987633/#:~:text=match%20at%20L191%20MAGEA4%20MHD,We%20also%20defined')
  35. AnnotationURLCitation(end_index=11027, start_index=10875, title='Structural basis for RAD18 regulation by MAGEA4 and its implications for RING ubiquitin ligase binding by MAGE family proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10987633/#:~:text=match%20at%20L173%20,damage%2C%20through%20the%20stabilisation%20of')
  36. AnnotationURLCitation(end_index=11289, start_index=11128, title='Structural basis for RAD18 regulation by MAGEA4 and its implications for RING ubiquitin ligase binding by MAGE family proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10987633/#:~:text=highly%20specific%20to%20MAGEA4%20,term%20maintenance%20of%20spermatogenesis')
  37. AnnotationURLCitation(end_index=11669, start_index=11517, title='Structural basis for RAD18 regulation by MAGEA4 and its implications for RING ubiquitin ligase binding by MAGE family proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10987633/#:~:text=match%20at%20L173%20,damage%2C%20through%20the%20stabilisation%20of')
  38. AnnotationURLCitation(end_index=11928, start_index=11771, title='Structural basis for RAD18 regulation by MAGEA4 and its implications for RING ubiquitin ligase binding by MAGE family proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10987633/#:~:text=match%20at%20L186%20MAGEA4%20in,drug%20target%20for%20cancer%20therapies')
  39. AnnotationURLCitation(end_index=12462, start_index=12292, title='Expression of RAD18 in cancer - Summary - The Human Protein Atlas', type='url_citation', url='https://www.proteinatlas.org/ENSG00000070950-RAD18/cancer#:~:text=normal%20tissue,IMMUNOHISTOCHEMISTRY%20DATA%20RELIABILITY%20Data%20reliability')
  40. AnnotationURLCitation(end_index=12862, start_index=12716, title='High RAD18 Expression is Associated with Disease Progression and Poor Prognosis in Patients with Gastric Cancer - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/32356270/#:~:text=Results%3A%20RAD18%20expression%20was%20predominantly,0061%29%20and')
  41. AnnotationURLCitation(end_index=13386, start_index=13243, title='ATR limits Rad18-mediated PCNA monoubiquitination to preserve replication fork and telomerase-independent telomere stability | The EMBO Journal', type='url_citation', url='https://www.embopress.org/doi/10.1038/s44318-024-00066-9#:~:text=2005%29,the%20precise%20molecular%20crosstalk%20between')
  42. AnnotationURLCitation(end_index=13687, start_index=13499, title='ATR limits Rad18-mediated PCNA monoubiquitination to preserve replication fork and telomerase-independent telomere stability | The EMBO Journal', type='url_citation', url='https://www.embopress.org/doi/10.1038/s44318-024-00066-9#:~:text=phosphorylates%20human%20Rad18%20at%20Ser403%2C,mediated%20PCNA%20monoubiquitination.%20Consequently')
  43. AnnotationURLCitation(end_index=14045, start_index=13857, title='ATR limits Rad18-mediated PCNA monoubiquitination to preserve replication fork and telomerase-independent telomere stability | The EMBO Journal', type='url_citation', url='https://www.embopress.org/doi/10.1038/s44318-024-00066-9#:~:text=phosphorylates%20human%20Rad18%20at%20Ser403%2C,mediated%20PCNA%20monoubiquitination.%20Consequently')
  44. AnnotationURLCitation(end_index=14327, start_index=14162, title='ATR limits Rad18-mediated PCNA monoubiquitination to preserve replication fork and telomerase-independent telomere stability | The EMBO Journal', type='url_citation', url='https://www.embopress.org/doi/10.1038/s44318-024-00066-9#:~:text=ATR%20activation%20and%20Rad18,of%20this%20interplay%2C%20remain%20unresolved')
  45. AnnotationURLCitation(end_index=15212, start_index=15047, title='ATR limits Rad18-mediated PCNA monoubiquitination to preserve replication fork and telomerase-independent telomere stability | The EMBO Journal', type='url_citation', url='https://www.embopress.org/doi/10.1038/s44318-024-00066-9#:~:text=ATR%20activation%20and%20Rad18,of%20this%20interplay%2C%20remain%20unresolved')
  46. AnnotationURLCitation(end_index=15678, start_index=15517, title='ATR limits Rad18-mediated PCNA monoubiquitination to preserve replication fork and telomerase-independent telomere stability | The EMBO Journal', type='url_citation', url='https://www.embopress.org/doi/10.1038/s44318-024-00066-9#:~:text=ultraviolet%20%28UV%29%20radiation,suggest%20that%20ATR%20may%20constrain')
  47. AnnotationURLCitation(end_index=15827, start_index=15679, title='ATR limits Rad18-mediated PCNA monoubiquitination to preserve replication fork and telomerase-independent telomere stability | The EMBO Journal', type='url_citation', url='https://www.embopress.org/doi/10.1038/s44318-024-00066-9#:~:text=%28Fig,detrimental%20consequence%20of%20replication%20stress')
  48. AnnotationURLCitation(end_index=16081, start_index=15907, title='ATR limits Rad18-mediated PCNA monoubiquitination to preserve replication fork and telomerase-independent telomere stability | The EMBO Journal', type='url_citation', url='https://www.embopress.org/doi/10.1038/s44318-024-00066-9#:~:text=The%20exact%20molecular%20interplay%20between,to%20maintain%20replication%20fork%20and')
  49. AnnotationURLCitation(end_index=16262, start_index=16082, title='ATR limits Rad18-mediated PCNA monoubiquitination to preserve replication fork and telomerase-independent telomere stability | The EMBO Journal', type='url_citation', url='https://www.embopress.org/doi/10.1038/s44318-024-00066-9#:~:text=Rad18%20at%20Ser403%20during%20replication,ATR%E2%80%99s%20role%20extends%20to%20maintaining')
  50. AnnotationURLCitation(end_index=16725, start_index=16565, title='RAD18 O-GlcNAcylation promotes translesion DNA synthesis and homologous recombination repair | Cell Death & Disease', type='url_citation', url='https://www.nature.com/articles/s41419-024-06700-y#:~:text=how%20the%20regulatory%20mechanism%20of,optimal%20RAD18%20accumulation%20at%20DNA')
  51. AnnotationURLCitation(end_index=16870, start_index=16726, title='RAD18 O-GlcNAcylation promotes translesion DNA synthesis and homologous recombination repair | Cell Death & Disease', type='url_citation', url='https://www.nature.com/articles/s41419-024-06700-y#:~:text=RAD18%20at%20DNA%20double,establishing%20a%20new%20rationale%20to')
  52. AnnotationURLCitation(end_index=17151, start_index=17020, title='RAD18 O-GlcNAcylation promotes translesion DNA synthesis and homologous recombination repair | Cell Death & Disease', type='url_citation', url='https://www.nature.com/articles/s41419-024-06700-y#:~:text=damage%20sites,and%20RAD51C%20binding%20ability%20of')
  53. AnnotationURLCitation(end_index=17498, start_index=17338, title='RAD18 O-GlcNAcylation promotes translesion DNA synthesis and homologous recombination repair | Cell Death & Disease', type='url_citation', url='https://www.nature.com/articles/s41419-024-06700-y#:~:text=how%20the%20regulatory%20mechanism%20of,optimal%20RAD18%20accumulation%20at%20DNA')
  54. AnnotationURLCitation(end_index=17762, start_index=17618, title='RAD18 O-GlcNAcylation promotes translesion DNA synthesis and homologous recombination repair | Cell Death & Disease', type='url_citation', url='https://www.nature.com/articles/s41419-024-06700-y#:~:text=RAD18%20at%20DNA%20double,establishing%20a%20new%20rationale%20to')
  55. AnnotationURLCitation(end_index=18246, start_index=18098, title='Structural basis for RAD18 regulation by MAGEA4 and its implications for RING ubiquitin ligase binding by MAGE family proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10987633/#:~:text=,inhibits%20degradative%20RAD18%20autoubiquitination%2C%20which')
  56. AnnotationURLCitation(end_index=18365, start_index=18247, title='Structural basis for RAD18 regulation by MAGEA4 and its implications for RING ubiquitin ligase binding by MAGE family proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10987633/#:~:text=,degradative%20autoubiquitination')
  57. AnnotationURLCitation(end_index=19304, start_index=19147, title='RAD18 opposes transcription-associated genome instability through FANCD2 recruitment - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9767342/#:~:text=RAD18%20is%20a%20conserved%20E3,conductor%20at%20the%20replication%20fork')
  58. AnnotationURLCitation(end_index=19903, start_index=19768, title='Enhanced Genomic Instability and Defective Postreplication Repair in RAD18 Knockout Mouse Embryonic Stem Cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC151530/#:~:text=Enhanced%20Genomic%20Instability%20and%20Defective,2')
  59. AnnotationURLCitation(end_index=20312, start_index=20168, title='Dysfunction of human Rad18 results in defective postreplication repair and hypersensitivity to multiple mutagens - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC16647/#:~:text=hypersensitivity%20to%20multiple%20mutagens%20,Oligonucleotide')
  60. AnnotationURLCitation(end_index=20819, start_index=20666, title='RAD18 opposes transcription-associated genome instability through FANCD2 recruitment - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9767342/#:~:text=pathways%20to%20preserve%20genome%20stability,replication%20conflicts')
  61. AnnotationURLCitation(end_index=21175, start_index=21022, title='RAD18 opposes transcription-associated genome instability through FANCD2 recruitment - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9767342/#:~:text=pathways%20to%20preserve%20genome%20stability,replication%20conflicts')
  62. AnnotationURLCitation(end_index=21497, start_index=21339, title='RAD18 opposes transcription-associated genome instability through FANCD2 recruitment - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9767342/#:~:text=conflicts%20and%20accumulate%20DNA%3ARNA%20hybrids,replication%20conflicts')
  63. AnnotationURLCitation(end_index=21982, start_index=21821, title='RAD18 opposes transcription-associated genome instability through FANCD2 recruitment - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9767342/#:~:text=DNA%20replication%20is%20a%20vulnerable,at%20difficult%20to%20replicate%20and')
  64. AnnotationURLCitation(end_index=22128, start_index=21983, title='RAD18 opposes transcription-associated genome instability through FANCD2 recruitment - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9767342/#:~:text=to%20recruit%20the%20Fanconi%20Anemia,replication%20conflicts')
  65. AnnotationURLCitation(end_index=22881, start_index=22717, title='RAD18 directs DNA\xa0double-strand break repair by homologous recombination to post-replicative chromatin - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11260465/#:~:text=classical%20role%2C%20RAD18%20has%20been,and%20limits%20the%20distribution%20of')
  66. AnnotationURLCitation(end_index=23201, start_index=23037, title='RAD18 directs DNA\xa0double-strand break repair by homologous recombination to post-replicative chromatin - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11260465/#:~:text=classical%20role%2C%20RAD18%20has%20been,and%20limits%20the%20distribution%20of')
  67. AnnotationURLCitation(end_index=23429, start_index=23265, title='RAD18 directs DNA\xa0double-strand break repair by homologous recombination to post-replicative chromatin - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11260465/#:~:text=classical%20role%2C%20RAD18%20has%20been,and%20limits%20the%20distribution%20of')
  68. AnnotationURLCitation(end_index=23915, start_index=23751, title='RAD18 directs DNA\xa0double-strand break repair by homologous recombination to post-replicative chromatin - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11260465/#:~:text=classical%20role%2C%20RAD18%20has%20been,and%20limits%20the%20distribution%20of')
  69. AnnotationURLCitation(end_index=24299, start_index=24146, title='RAD18 directs DNA double-strand break repair by homologous recombination to post-replicative chromatin - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/38884202/#:~:text=RAD18%20is%20an%20E3%20ubiquitin,to%20DNA%20breaks%2C%20interaction%20with')
  70. AnnotationURLCitation(end_index=24477, start_index=24300, title='RAD18 directs DNA double-strand break repair by homologous recombination to post-replicative chromatin - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/38884202/#:~:text=to%20DNA%20lesions%20by%20monoubiquitination,Surprisingly%2C%20suppression%20of%2053BP1%20function')
  71. AnnotationURLCitation(end_index=24815, start_index=24651, title='RAD18 directs DNA\xa0double-strand break repair by homologous recombination to post-replicative chromatin - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11260465/#:~:text=classical%20role%2C%20RAD18%20has%20been,and%20limits%20the%20distribution%20of')
  72. AnnotationURLCitation(end_index=25263, start_index=25114, title='Exploring RAD18-dependent replication of damaged DNA and discontinuities: A collection of advanced tools - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0168165623002122#:~:text=Exploring%20RAD18,Exploring%20the%20role%20and')
  73. AnnotationURLCitation(end_index=25413, start_index=25264, title='DNA repair factor RAD18 and DNA polymerase Polκ confer tolerance of oncogenic DNA replication stress - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/28835467/#:~:text=DNA%20repair%20factor%20RAD18%20and,h%2C%20and%20cell%20lysates%20were')
  74. AnnotationURLCitation(end_index=26265, start_index=26102, title='DNA repair factor RAD18 and DNA polymerase Polκ confer tolerance of oncogenic DNA replication stress - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5626543/#:~:text=Skip%20to%20main%20content%20J,Rottmayer%20%5E%7B1%7D%2C%20Anastasia%20Zlatanou')
  75. AnnotationURLCitation(end_index=26589, start_index=26426, title='DNA repair factor RAD18 and DNA polymerase Polκ confer tolerance of oncogenic DNA replication stress - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5626543/#:~:text=Skip%20to%20main%20content%20J,Rottmayer%20%5E%7B1%7D%2C%20Anastasia%20Zlatanou')
  76. AnnotationURLCitation(end_index=26855, start_index=26684, title='Rad18 guides polη to replication stalling sites through physical interaction and PCNA monoubiquitination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC522788/#:~:text=Rad18%20guides%20pol%CE%B7%20to%20replication,detectable%20levels%20of%20Rad18%20protein')
  77. AnnotationURLCitation(end_index=27142, start_index=26985, title='RAD18 opposes transcription-associated genome instability through FANCD2 recruitment - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9767342/#:~:text=RAD18%20is%20a%20conserved%20E3,conductor%20at%20the%20replication%20fork')
  78. AnnotationURLCitation(end_index=27563, start_index=27402, title='RAD18 opposes transcription-associated genome instability through FANCD2 recruitment - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9767342/#:~:text=DNA%20replication%20is%20a%20vulnerable,at%20difficult%20to%20replicate%20and')
  79. AnnotationURLCitation(end_index=27717, start_index=27564, title='RAD18 opposes transcription-associated genome instability through FANCD2 recruitment - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9767342/#:~:text=pathways%20to%20preserve%20genome%20stability,replication%20conflicts')
  80. AnnotationURLCitation(end_index=28789, start_index=28643, title='High RAD18 Expression is Associated with Disease Progression and Poor Prognosis in Patients with Gastric Cancer - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/32356270/#:~:text=Results%3A%20RAD18%20expression%20was%20predominantly,0061%29%20and')
  81. AnnotationURLCitation(end_index=29085, start_index=28939, title='High RAD18 Expression is Associated with Disease Progression and Poor Prognosis in Patients with Gastric Cancer - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/32356270/#:~:text=Results%3A%20RAD18%20expression%20was%20predominantly,0061%29%20and')
  82. AnnotationURLCitation(end_index=29425, start_index=29245, title='A positive feedback loop: RAD18-YAP-TGF-β between triple-negative breast cancer and macrophages regulates cancer stemness and progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9005530/#:~:text=tumor%20microenvironment%2C%20remains%20elusive,nude%20mice%2C%20RAD18%20promoted%20subcutaneous')
  83. AnnotationURLCitation(end_index=29726, start_index=29573, title='A positive feedback loop: RAD18-YAP-TGF-β between triple-negative breast cancer and macrophages regulates cancer stemness and progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9005530/#:~:text=As%20a%20key%20regulator%20of,RAD18%20facilitated%20a%20highly%20stem')
  84. AnnotationURLCitation(end_index=30041, start_index=29861, title='A positive feedback loop: RAD18-YAP-TGF-β between triple-negative breast cancer and macrophages regulates cancer stemness and progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9005530/#:~:text=tumor%20microenvironment%2C%20remains%20elusive,nude%20mice%2C%20RAD18%20promoted%20subcutaneous')
  85. AnnotationURLCitation(end_index=30192, start_index=30042, title='A positive feedback loop: RAD18-YAP-TGF-β between triple-negative breast cancer and macrophages regulates cancer stemness and progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9005530/#:~:text=correlated%20with%20prognosis,of%20the%20stemness%20phenotype%20by')
  86. AnnotationURLCitation(end_index=30584, start_index=30434, title='A positive feedback loop: RAD18-YAP-TGF-β between triple-negative breast cancer and macrophages regulates cancer stemness and progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9005530/#:~:text=correlated%20with%20prognosis,of%20the%20stemness%20phenotype%20by')
  87. AnnotationURLCitation(end_index=31192, start_index=31063, title='Role of Rad18 in B cell activation and lymphomagenesis | Scientific Reports', type='url_citation', url='https://www.nature.com/articles/s41598-024-57018-w#:~:text=Several%20studies%20have%20addressed%20the,induced')
  88. AnnotationURLCitation(end_index=31338, start_index=31193, title='Role of Rad18 in B cell activation and lymphomagenesis | Scientific Reports', type='url_citation', url='https://www.nature.com/articles/s41598-024-57018-w#:~:text=cooperates%20with%20MAGE,affects%20migration%20and%20invasion%20of')
  89. AnnotationURLCitation(end_index=31666, start_index=31521, title='Role of Rad18 in B cell activation and lymphomagenesis | Scientific Reports', type='url_citation', url='https://www.nature.com/articles/s41598-024-57018-w#:~:text=cooperates%20with%20MAGE,affects%20migration%20and%20invasion%20of')
  90. AnnotationURLCitation(end_index=32068, start_index=31888, title='RAD18 confers radioresistance of esophagus squamous cell carcinoma through regulating p‐DNA‐PKcs - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9582675/#:~:text=RAD18%20confers%20radioresistance%20of%20esophagus,in%20Dulbecco%27s%20Modified%20Eagle%20Medium')
  91. AnnotationURLCitation(end_index=32440, start_index=32287, title='RAD18 promotes colorectal cancer metastasis by activating the epithelial-mesenchymal transition pathway - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7251712/#:~:text=RAD18%20promotes%20colorectal%20cancer%20metastasis,4%7D%2C%20Jundong')
  92. AnnotationURLCitation(end_index=32970, start_index=32785, title='A series of xanthenes inhibiting Rad6 function and Rad6-Rad18 interaction in the PCNA ubiquitination cascade - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8958325/#:~:text=Ubiquitination%20of%20proliferating%20cell%20nuclear,important%20for%20different%20activities%20along')
  93. AnnotationURLCitation(end_index=33108, start_index=32971, title='The E3 ligase RAD18-mediated ubiquitination of henipavirus matrix protein promotes its nuclear-cytoplasmic trafficking and viral egress - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/39628457/#:~:text=through%20a%20K63,infection%20is%20attenuated%20in%20RAD18')
  94. AnnotationURLCitation(end_index=33413, start_index=33228, title='A series of xanthenes inhibiting Rad6 function and Rad6-Rad18 interaction in the PCNA ubiquitination cascade - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8958325/#:~:text=Ubiquitination%20of%20proliferating%20cell%20nuclear,important%20for%20different%20activities%20along')
  95. AnnotationURLCitation(end_index=33748, start_index=33611, title='The E3 ligase RAD18-mediated ubiquitination of henipavirus matrix protein promotes its nuclear-cytoplasmic trafficking and viral egress - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/39628457/#:~:text=through%20a%20K63,infection%20is%20attenuated%20in%20RAD18')
  96. AnnotationURLCitation(end_index=34117, start_index=33951, title='EP3237444A1 - Use of rad18 inhibitors in the treatment of tumors - Google Patents', type='url_citation', url='https://patents.google.com/patent/EP3237444A1/en#:~:text=Patents%20patents.google.com%20%20EP3237444A1%20,A1%20EP3237444%20A1%20EP%203237444A1')
  97. AnnotationURLCitation(end_index=34198, start_index=34118, title='U.S. Patent for Use of Rad18 inhibitors in the treatment of tumors Patent (Patent # 11,203,757 issued December 21, 2021) - Justia Patents Search', type='url_citation', url='https://patents.justia.com/patent/11203757#:~:text=U,The')
  98. AnnotationURLCitation(end_index=34990, start_index=34811, title='The E3 ligase RAD18-mediated ubiquitination of henipavirus matrix protein promotes its nuclear-cytoplasmic trafficking and viral egress - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/39628457/#:~:text=ubiquitination%20cascade%20have%20remained%20elusive,modification%20crucial%20for%20M%27s%20function')
  99. AnnotationURLCitation(end_index=35387, start_index=35224, title='The E3 ligase RAD18-mediated ubiquitination of henipavirus matrix protein promotes its nuclear-cytoplasmic trafficking and viral egress - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/39628457/#:~:text=utilizes%20a%20ubiquitination%20complex%20involving,Conversely%2C%20disrupting%20the')
  100. AnnotationURLCitation(end_index=35672, start_index=35547, title='The E3 ligase RAD18-mediated ubiquitination of henipavirus matrix protein promotes its nuclear-cytoplasmic trafficking and viral egress - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/39628457/#:~:text=RAD18,infection%20is%20attenuated%20in%20RAD18')
  101. AnnotationURLCitation(end_index=35990, start_index=35853, title='The E3 ligase RAD18-mediated ubiquitination of henipavirus matrix protein promotes its nuclear-cytoplasmic trafficking and viral egress - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/39628457/#:~:text=through%20a%20K63,infection%20is%20attenuated%20in%20RAD18')
  102. AnnotationURLCitation(end_index=36257, start_index=36120, title='The E3 ligase RAD18-mediated ubiquitination of henipavirus matrix protein promotes its nuclear-cytoplasmic trafficking and viral egress - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/39628457/#:~:text=through%20a%20K63,infection%20is%20attenuated%20in%20RAD18')
  103. AnnotationURLCitation(end_index=37000, start_index=36836, title='The E3 ligase RAD18-mediated ubiquitination of henipavirus matrix protein promotes its nuclear-cytoplasmic trafficking and viral egress - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/39628457/#:~:text=plasma%20membranes%20for%20effective%20viral,infection%20is%20attenuated%20in%20RAD18')
  104. AnnotationURLCitation(end_index=37521, start_index=37364, title='RAD18 opposes transcription-associated genome instability through FANCD2 recruitment - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9767342/#:~:text=RAD18%20is%20a%20conserved%20E3,conductor%20at%20the%20replication%20fork')
  105. AnnotationURLCitation(end_index=37773, start_index=37660, title='RAD18 opposes transcription-associated genome instability through FANCD2 recruitment - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9767342/#:~:text=replication%20%28BIR%29%20,12')
  106. AnnotationURLCitation(end_index=38339, start_index=38186, title='RAD18 opposes transcription-associated genome instability through FANCD2 recruitment - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9767342/#:~:text=pathways%20to%20preserve%20genome%20stability,replication%20conflicts')
  107. AnnotationURLCitation(end_index=38824, start_index=38668, title='RAD18 directs DNA\xa0double-strand break repair by homologous recombination to post-replicative chromatin - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11260465/#:~:text=RAD18%20is%20an%20E3%20ubiquitin,and%20limits%20the%20distribution%20of')
  108. AnnotationURLCitation(end_index=39356, start_index=39212, title='RAD18 O-GlcNAcylation promotes translesion DNA synthesis and homologous recombination repair | Cell Death & Disease', type='url_citation', url='https://www.nature.com/articles/s41419-024-06700-y#:~:text=RAD18%20at%20DNA%20double,establishing%20a%20new%20rationale%20to')
  109. AnnotationURLCitation(end_index=39515, start_index=39357, title='RAD18 O-GlcNAcylation promotes translesion DNA synthesis and homologous recombination repair | Cell Death & Disease', type='url_citation', url='https://www.nature.com/articles/s41419-024-06700-y#:~:text=In%20this%20study%2C%20we%20identified,Although%20S130A%2FS164A%2FT468A%20%283A')
  110. AnnotationURLCitation(end_index=39863, start_index=39698, title='ATR limits Rad18-mediated PCNA monoubiquitination to preserve replication fork and telomerase-independent telomere stability | The EMBO Journal', type='url_citation', url='https://www.embopress.org/doi/10.1038/s44318-024-00066-9#:~:text=ATR%20activation%20and%20Rad18,of%20this%20interplay%2C%20remain%20unresolved')
  111. AnnotationURLCitation(end_index=40044, start_index=39864, title='ATR limits Rad18-mediated PCNA monoubiquitination to preserve replication fork and telomerase-independent telomere stability | The EMBO Journal', type='url_citation', url='https://www.embopress.org/doi/10.1038/s44318-024-00066-9#:~:text=Rad18%20at%20Ser403%20during%20replication,ATR%E2%80%99s%20role%20extends%20to%20maintaining')
  112. AnnotationURLCitation(end_index=40613, start_index=40465, title='Structural basis for RAD18 regulation by MAGEA4 and its implications for RING ubiquitin ligase binding by MAGE family proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10987633/#:~:text=,inhibits%20degradative%20RAD18%20autoubiquitination%2C%20which')
  113. AnnotationURLCitation(end_index=40732, start_index=40614, title='Structural basis for RAD18 regulation by MAGEA4 and its implications for RING ubiquitin ligase binding by MAGE family proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10987633/#:~:text=,degradative%20autoubiquitination')
  114. AnnotationURLCitation(end_index=41098, start_index=40941, title='Structural basis for RAD18 regulation by MAGEA4 and its implications for RING ubiquitin ligase binding by MAGE family proteins - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10987633/#:~:text=match%20at%20L186%20MAGEA4%20in,drug%20target%20for%20cancer%20therapies')
  115. AnnotationURLCitation(end_index=41544, start_index=41398, title='Role of Rad18 in B cell activation and lymphomagenesis | Scientific Reports', type='url_citation', url='https://www.nature.com/articles/s41598-024-57018-w#:~:text=A%20recent%20study%20analysed%20the,of%20generation%20of%20B%20cell')
  116. AnnotationURLCitation(end_index=41797, start_index=41648, title='Role of Rad18 in B cell activation and lymphomagenesis | Scientific Reports', type='url_citation', url='https://www.nature.com/articles/s41598-024-57018-w#:~:text=studies%20have%20shown%20different%20roles,We%20find%20no%20activation')
  117. AnnotationURLCitation(end_index=41927, start_index=41798, title='Role of Rad18 in B cell activation and lymphomagenesis | Scientific Reports', type='url_citation', url='https://www.nature.com/articles/s41598-024-57018-w#:~:text=Several%20studies%20have%20addressed%20the,induced')
  118. AnnotationURLCitation(end_index=42230, start_index=42070, title='Role of Rad18 in B cell activation and lymphomagenesis | Scientific Reports', type='url_citation', url='https://www.nature.com/articles/s41598-024-57018-w#:~:text=defects%20or%20survival%20differences%20between,other%20pathways%20in%20B%20cells')
  119. AnnotationURLCitation(end_index=42645, start_index=42492, title='A positive feedback loop: RAD18-YAP-TGF-β between triple-negative breast cancer and macrophages regulates cancer stemness and progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9005530/#:~:text=As%20a%20key%20regulator%20of,RAD18%20facilitated%20a%20highly%20stem')
  120. AnnotationURLCitation(end_index=42817, start_index=42646, title='A positive feedback loop: RAD18-YAP-TGF-β between triple-negative breast cancer and macrophages regulates cancer stemness and progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9005530/#:~:text=tumor%20microenvironment%2C%20remains%20elusive,this%20loop%20and%20suppresses%20cancer')
  121. AnnotationURLCitation(end_index=43118, start_index=42968, title='Role of Rad18 in B cell activation and lymphomagenesis | Scientific Reports', type='url_citation', url='https://www.nature.com/articles/s41598-024-57018-w#:~:text=of%20the%20Fanconi%20anaemia%20pathway,play%20a%20role%20during%20viral')
  122. AnnotationURLCitation(end_index=43842, start_index=43676, title='EP3237444A1 - Use of rad18 inhibitors in the treatment of tumors - Google Patents', type='url_citation', url='https://patents.google.com/patent/EP3237444A1/en#:~:text=Patents%20patents.google.com%20%20EP3237444A1%20,A1%20EP3237444%20A1%20EP%203237444A1')
  123. AnnotationURLCitation(end_index=43923, start_index=43843, title='U.S. Patent for Use of Rad18 inhibitors in the treatment of tumors Patent (Patent # 11,203,757 issued December 21, 2021) - Justia Patents Search', type='url_citation', url='https://patents.justia.com/patent/11203757#:~:text=U,The')
  124. AnnotationURLCitation(end_index=45002, start_index=44845, title='RAD18 opposes transcription-associated genome instability through FANCD2 recruitment - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9767342/#:~:text=RAD18%20is%20a%20conserved%20E3,conductor%20at%20the%20replication%20fork')
  125. AnnotationURLCitation(end_index=45116, start_index=45003, title='RAD18 opposes transcription-associated genome instability through FANCD2 recruitment - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9767342/#:~:text=replication%20%28BIR%29%20,12')