The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
Human SHLD2—formerly FAM35A and also called RINN2—is correctly identified as UniProt Q86V20, the single-stranded-DNA-binding subunit of the four-protein shieldin complex. The literature identity matches the supplied description and domain annotations; no conflicting gene with the same symbol was encountered. SHLD2 is not an enzyme or transporter. Its primary function is to act as a non-catalytic DNA-binding/scaffolding component that recognizes partially resected DNA double-strand-break (DSB) ends and helps shield them from excessive 5′-end resection. This shifts repair away from homologous recombination (HR) and toward end protection, fill-in synthesis, and non-homologous end joining (NHEJ). (tomida2018fam35aassociates pages 9-10, tomida2018fam35aassociates pages 1-3, zhou2023dynamicsofthe pages 1-5)
The concise evidence map below distinguishes SHLD2-specific findings from observations made using shieldin as a complex.
| Annotation category | SHLD2 functional annotation | Evidence scope and strength |
|---|---|---|
| Verified identity and aliases | Human SHLD2 is the protein originally characterized as FAM35A and also named RINN2; it is the REV7-associated subunit corresponding to the supplied UniProt accession Q86V20. No conflicting same-symbol protein was identified. (tomida2018fam35aassociates pages 9-10, tomida2018fam35aassociates pages 1-3) | Alias correspondence is supported by peer-reviewed human-cell literature; the accession mapping comes from the supplied UniProt identity context. |
| Molecular class | Non-enzymatic, structural DNA-binding/adaptor subunit of shieldin. No catalytic reaction, enzymatic substrate, or transporter activity is known. Its relevant molecular substrate is resected single-stranded DNA (ssDNA) at DNA double-strand breaks. (zhou2023dynamicsofthe pages 8-11, zhou2023dynamicsofthe pages 1-5) | SHLD2-specific functional classification; no kinetic constants or catalytic activity have been reported in the gathered evidence. |
| Domain architecture | FAM35A/SHLD2 was predicted to contain an unstructured N-terminal region with DNA-damage-regulated modification sites and a C-terminal region containing three OB folds resembling those of the RPA large subunit. This agrees with the supplied FAM35A, SHLD2_C, SHLD2_OB1 and SHLD2_OB2 annotations. (tomida2018fam35aassociates pages 1-3) | Peer-reviewed, SHLD2-specific sequence and structural inference; the gathered evidence does not provide a full-length high-resolution structure. |
| Complex partners | Shieldin comprises REV7, SHLD1/C20orf196, SHLD2/FAM35A and SHLD3/CTC-534A2.2. FAM35A was identified by proteomics and co-immunoprecipitation as a REV7-associated protein connected to the 53BP1–RIF1 repair axis. Shieldin also functionally interacts with CST, which recruits DNA polymerase-α–primase. (tomida2018fam35aassociates pages 1-3, zhou2023dynamicsofthe pages 1-5) | REV7 association is SHLD2-specific and peer reviewed; CST–Polα coupling is principally shieldin-complex-level evidence. |
| Direct biochemical activity | SHLD2's OB folds mediate binding to ssDNA, enabling shieldin to recognize and protect partially resected DNA ends. The gathered evidence supplies no purified-protein affinity constant or sequence-specificity measurement; therefore, precise nucleotide preference and binding kinetics remain undefined. (zhou2023dynamicsofthe pages 8-11) | The ssDNA-binding assignment is SHLD2-specific, but detailed biochemistry is limited in the retrieved passages. |
| Nuclear localization and recruitment | FAM35A relocalizes within damaged cell nuclei. Shieldin accumulates at a subset of 53BP1-positive DSBs, mainly during G1, after limited MRE11/CtIP-dependent resection creates ssDNA; recruitment is delayed relative to early 53BP1/DYNLL1 signaling. (tomida2018fam35aassociates pages 1-3, zhou2023dynamicsofthe pages 8-11, zhou2023dynamicsofthe pages 1-5) | Nuclear damage relocalization is SHLD2-specific and peer reviewed; detailed timing and cell-cycle data use SHLD1 as a shieldin marker in a 2023 preprint. |
| Pathway role | In the 53BP1–RIF1–shieldin–CST–Polα axis, SHLD2 helps shieldin bind resected ssDNA, suppress extended 5′-end resection, and promote CST/Polα-dependent fill-in. This limits RAD51 loading and homologous recombination while favoring end protection and non-homologous end joining. (zhou2023dynamicsofthe pages 1-5, tomida2018fam35aassociates pages 9-10, zhou2023dynamicsofthe pages 11-15) | Central model supported by multiple shieldin studies; the exact ASTE1-cleavage sequence proposed in 2023 remains hypothetical. |
| Experimental phenotypes | FAM35A depletion sensitized otherwise repair-proficient cells to DNA-damaging agents but increased camptothecin resistance in BRCA1-mutant cells. Loss permits greater end resection and HR or alternative end joining; shieldin loss reduces PARP-inhibitor-associated chromosome radials in BRCA1-deficient models. (tomida2018fam35aassociates pages 9-10, tomida2018fam35aassociates pages 1-3, zhou2023dynamicsofthe pages 8-11) | FAM35A knockdown phenotypes are SHLD2-specific and peer reviewed; chromosome-radial and recruitment experiments are largely complex-level. |
| Cancer and PARP-inhibitor relevance | Loss of SHLD2/shieldin can partially restore resection and HR in BRCA1-deficient cells, producing resistance to olaparib/PARP inhibition. The PARPi-resistant BRCA1-mutant HCC1937 line lacks FAM35A exons 1–2, and FAM35A suppression alleviated olaparib sensitivity in BRCA1-defective U2OS cells. SHLD2 is therefore a mechanistic candidate resistance biomarker, not a clinically validated stand-alone diagnostic or drug target. (tomida2018fam35aassociates pages 9-10, tomida2018fam35aassociates pages 1-3) | Peer-reviewed preclinical evidence; no SHLD2-directed therapy or prospective clinical validation was identified. |
| Quantitative evidence | FAM35A alterations were below 5% in most surveyed cancers but deletions occurred in approximately 6–13% of prostate cancers, with lower expression in metastatic cases. In the 2023 model, shieldin/SHLD1 appeared at about 20% of 53BP1 foci, compared with about 90% for DYNLL1, and became detectable more than an hour later; most foci occurred in G1. (tomida2018fam35aassociates pages 9-10, zhou2023dynamicsofthe pages 8-11) | Cancer frequencies derive from the 2018 peer-reviewed study; focus percentages and timing derive from a non-peer-reviewed 2023 preprint and are not SHLD2-only measurements. |
| Evidence limitations | Much of the mechanistic literature perturbs or tracks SHLD1, REV7, or shieldin as a whole, so not every localization or repair phenotype can be assigned uniquely to SHLD2. The 2023 recruitment model is a bioRxiv preprint; SHLD2 lacks reported catalytic activity, detailed substrate specificity, binding constants, a complete full-length experimental structure, and prospective clinical biomarker validation in the gathered evidence. (zhou2023dynamicsofthe pages 25-27, zhou2023dynamicsofthe pages 8-11, zhou2023dynamicsofthe pages 11-15) | Separates direct SHLD2 evidence from complex-level inference and peer-reviewed findings from preprint claims. |
Table: Concise evidence map for human SHLD2/Q86V20, separating SHLD2-specific findings from shieldin-complex inference and peer-reviewed results from the 2023 preprint.
The target is Homo sapiens SHLD2/FAM35A/RINN2, not a similarly named protein from another organism. The foundational human-cell study identified FAM35A as a previously uncharacterized REV7-associated DNA-repair protein; subsequent shieldin nomenclature designated it SHLD2/RINN2. This is fully concordant with the supplied Q86V20 record: shieldin complex subunit 2, formerly protein FAM35A and REV7-interacting novel NHEJ regulator 2. (tomida2018fam35aassociates pages 9-10, tomida2018fam35aassociates pages 1-3)
The reported architecture also matches the supplied InterPro/Pfam annotations. Sequence analysis found an unstructured N-terminal region containing DNA-damage-associated modification sites and a C-terminal half with three oligonucleotide/oligosaccharide-binding (OB) folds resembling the nucleic-acid-binding folds of RPA. These observations align with the supplied FAM35A, SHLD2_C, SHLD2_OB1, SHLD2_OB2, and second-OB-fold annotations. (tomida2018fam35aassociates pages 1-3)
SHLD2 is best classified as a non-enzymatic ssDNA-binding adapter/end-protection factor. There is no known catalyzed reaction, catalytic substrate, transported substrate, or signaling-enzyme activity. Its relevant molecular ligand is single-stranded DNA generated by limited resection at DSB ends. Shieldin binds ssDNA through SHLD2’s OB-fold region, allowing the complex to occupy and protect exposed DNA overhangs. (zhou2023dynamicsofthe pages 8-11, zhou2023dynamicsofthe pages 1-5)
Available evidence establishes ssDNA recognition but does not define a nucleotide-sequence preference, minimum tract length, dissociation constant, or catalytic turnover. It is therefore more accurate to call ssDNA the protein’s binding substrate/ligand, rather than an enzymatic substrate. Likewise, the retrieved evidence does not provide a complete high-resolution structure of full-length SHLD2; much of the structural assignment derives from OB-fold prediction and shieldin-complex studies. (tomida2018fam35aassociates pages 1-3, zhou2023dynamicsofthe pages 8-11)
Shieldin contains REV7, SHLD1/C20orf196, SHLD2/FAM35A, and SHLD3/CTC-534A2.2. FAM35A was discovered through proteomic purification and co-immunoprecipitation as a REV7-associated protein linked to the 53BP1–RIF1 repair network. Within this assembly, SHLD2 supplies the principal ssDNA-recognition function, while the other components organize recruitment and complex assembly. (tomida2018fam35aassociates pages 1-3, zhou2023dynamicsofthe pages 1-5)
The broader interaction hierarchy is:
DSB chromatin → 53BP1 → RIF1 → shieldin (REV7–SHLD1–SHLD2–SHLD3) → CST (CTC1–STN1–TEN1) → DNA polymerase-α–primase.
This architecture couples recognition of a partially processed DNA end to protection and fill-in synthesis. (zhou2023dynamicsofthe pages 1-5)
SHLD2 acts primarily in the nucleus at sites of DNA damage. FAM35A relocalizes in damaged nuclei, and shieldin accumulates in foci at a subset of 53BP1-positive DSBs. Recruitment occurs downstream of limited MRE11/CtIP-dependent resection, which produces the ssDNA ligand recognized through SHLD2. (tomida2018fam35aassociates pages 1-3, zhou2023dynamicsofthe pages 8-11)
Recent mechanistic work suggests that shieldin recruitment is especially prominent in G1, consistent with a role in preventing inappropriate HR when a sister chromatid is unavailable. In a 2023 bioRxiv study using SHLD1 as the shieldin marker, shieldin appeared at approximately 20% of 53BP1 foci, compared with approximately 90% for the earlier factor DYNLL1; shieldin became evident more than an hour later and most detected foci occurred in G1. These measurements describe complex-level recruitment rather than SHLD2 alone and remain preprint evidence. (zhou2023dynamicsofthe pages 8-11)
DSB repair is governed partly by competition between NHEJ, which requires relatively protected ends, and HR, which requires 5′-strand resection to generate 3′ ssDNA tails for RAD51 loading. SHLD2 functions in the 53BP1–RIF1–shieldin axis, which restrains this resection and thereby opposes BRCA1-driven HR. (tomida2018fam35aassociates pages 9-10, osullivan2021chartingparp1dependent pages 252-255)
The current mechanistic model is:
The 2023 DYNLL1/MRE11 model adds temporal resolution: phosphorylated DYNLL1 removes MRE11 from damaged chromatin after limited resection, enabling shieldin loading onto newly generated ssDNA. The authors estimate that approximately 80% of DSB repair in their model does not require resection, whereas approximately 20% undergoes minimal MRE11/CtIP processing in G1 before shieldin protection. Proposed ASTE1 cleavage followed by CST–Polα fill-in is mechanistically plausible but should be treated as a model rather than an established SHLD2-catalyzed step. (zhou2023dynamicsofthe pages 11-15, zhou2023dynamicsofthe pages 25-27, zhou2023dynamicsofthe pages 27-35)
The strongest SHLD2-specific evidence comes from the peer-reviewed 2018 EMBO Journal study. Proteomic and co-immunoprecipitation experiments established FAM35A association with REV7; sequence analysis identified its OB-fold-rich C terminus; imaging showed damage-induced nuclear relocalization; and knockdown altered cellular responses to genotoxic agents. In otherwise repair-competent cells, depletion increased DNA-damage sensitivity, whereas in a BRCA1-mutant background it increased camptothecin resistance. These context-dependent phenotypes support a repair-pathway-choice function rather than a generic prosurvival role. (tomida2018fam35aassociates pages 9-10, tomida2018fam35aassociates pages 1-3)
Genetic loss of FAM35A/SHLD2 allows greater DNA-end resection in BRCA1-defective cells, enabling HR and/or alternative end joining and reducing sensitivity to olaparib and related damage. Suppression of FAM35A alleviated olaparib sensitivity in BRCA1-defective U2OS cells. At the shieldin-complex level, loss also reduces PARP-inhibitor-associated chromosome radials, whereas restored shieldin function reduces RAD51 foci and re-establishes PARP-inhibitor sensitivity. (tomida2018fam35aassociates pages 9-10, zhou2023dynamicsofthe pages 8-11)
An important interpretive limitation is that many later experiments use SHLD1 foci or perturb REV7/shieldin globally. Such findings establish the behavior of the complex but cannot always assign every localization or phenotype uniquely to SHLD2. (zhou2023dynamicsofthe pages 25-27, zhou2023dynamicsofthe pages 8-11)
SHLD2 is relevant to oncology chiefly through BRCA1 deficiency and PARP-inhibitor response. BRCA1-deficient tumors are vulnerable to PARP inhibition partly because they cannot carry out normal HR. Loss of 53BP1, RIF1, shieldin, or CST can restore sufficient end resection and HR-like repair to reduce this synthetic lethality. Accordingly, SHLD2 loss is a plausible mechanism of intrinsic or acquired PARP-inhibitor resistance. (zhou2023dynamicsofthe pages 1-5, tomida2018fam35aassociates pages 9-10, osullivan2021chartingparp1dependent pages 252-255)
The BRCA1-mutant HCC1937 cancer line contains a deep deletion involving FAM35A exons 1–2 and has anomalous PARP-inhibitor resistance, providing a concrete preclinical example. Cancer-genomic analysis in the foundational study found FAM35A alterations in less than 5% of most surveyed cancers, but deletions in approximately 6–13% of prostate cancers, together with lower expression in metastatic cases. These observations make SHLD2 a candidate stratification or resistance biomarker, although association does not establish clinical predictive utility. (tomida2018fam35aassociates pages 9-10, tomida2018fam35aassociates pages 1-3)
Current real-world relevance is therefore biomarker-oriented rather than SHLD2-directed therapy. PARP inhibitors are used clinically in homologous-recombination-deficient breast, ovarian, pancreatic, and prostate cancers, but no SHLD2-targeted drug, approved SHLD2 companion diagnostic, or prospectively validated SHLD2-only treatment algorithm was identified. The practical near-term application is inclusion of shieldin-pathway status in mechanistic studies or broader genomic analyses of PARP-inhibitor resistance. (tomida2018fam35aassociates pages 9-10, mcphersonUnknownyearvt05405usa pages 78-82)
The most directly relevant 2023 development was the proposed DYNLL1–MRE11 timing mechanism for shieldin recruitment. It refines the older view that shieldin simply blocks all resection: limited MRE11/CtIP processing may first generate the ssDNA needed for SHLD2 binding, after which shieldin prevents hyper-resection. This reconciles SHLD2’s ssDNA-binding requirement with shieldin’s overall anti-resection function. The study was posted in March 2023 and had not undergone peer review in the retrieved version. (zhou2023dynamicsofthe pages 1-5, zhou2023dynamicsofthe pages 8-11, zhou2023dynamicsofthe pages 11-15)
The 2024 literature increasingly frames PARP-inhibitor sensitivity and resistance through restoration of repair capacity and management of ssDNA gaps. In this framework, shieldin loss remains one route by which BRCA1-deficient cells regain resection and RAD51-dependent repair. However, contemporary tumor-model studies also show that resistance is heterogeneous and often driven by BRCA1/2 reversions or hypomorphic BRCA1 rather than shieldin loss alone. Thus authoritative interpretation favors treating SHLD2 as one node in a broader resistance network, not as a universal determinant. (zhou2023dynamicsofthe pages 1-5, tomida2018fam35aassociates pages 9-10)
The evidence supports a high-confidence primary annotation: SHLD2 is the ssDNA-binding effector of shieldin that protects partially resected DSB ends and promotes the 53BP1-dependent NHEJ state. Its most precise biochemical activity is nucleic-acid binding through OB folds; any description of SHLD2 as a nuclease, polymerase, kinase, or independent signaling molecule would be incorrect. (tomida2018fam35aassociates pages 1-3, zhou2023dynamicsofthe pages 8-11, zhou2023dynamicsofthe pages 1-5)
Important unresolved issues include the lack of detailed SHLD2 binding constants and sequence/structure specificity, incomplete full-length structural characterization, uncertainty about how frequently SHLD2 acts at endogenous lesion classes, and limited evidence separating SHLD2-specific phenotypes from those of shieldin as a whole. Its value as a clinical PARP-resistance biomarker also requires prospective patient-level validation. (zhou2023dynamicsofthe pages 25-27, zhou2023dynamicsofthe pages 8-11)
Overall, SHLD2/Q86V20 is a well-supported human nuclear DNA-repair adapter with a precise role in ssDNA recognition and DSB-end protection. Its mechanistic importance is established, whereas its clinical use remains investigational.
References
(tomida2018fam35aassociates pages 9-10): Junya Tomida, Kei‐ichi Takata, Sarita Bhetawal, Maria D Person, Hsueh‐Ping Chao, Dean G Tang, and Richard D Wood.
(tomida2018fam35aassociates pages 1-3): Junya Tomida, Kei‐ichi Takata, Sarita Bhetawal, Maria D Person, Hsueh‐Ping Chao, Dean G Tang, and Richard D Wood.
(zhou2023dynamicsofthe pages 1-5): Rui Zhou, Michelle L. Swift, Aleem Syed, Kaimeng Huang, Lisa Moreau, John A. Tainer, Panagiotis A. Konstantinopoulos, Alan D. D’Andrea, Yizhou Joseph He, and Dipanjan Chowdhury. Dynamics of the dynll1/mre11 complex regulates dna end resection and recruitment of the shieldin complex to dsbs. bioRxiv, Mar 2023. URL: https://doi.org/10.1101/2023.03.27.534416, doi:10.1101/2023.03.27.534416. This article has 0 citations.
(zhou2023dynamicsofthe pages 8-11): Rui Zhou, Michelle L. Swift, Aleem Syed, Kaimeng Huang, Lisa Moreau, John A. Tainer, Panagiotis A. Konstantinopoulos, Alan D. D’Andrea, Yizhou Joseph He, and Dipanjan Chowdhury. Dynamics of the dynll1/mre11 complex regulates dna end resection and recruitment of the shieldin complex to dsbs. bioRxiv, Mar 2023. URL: https://doi.org/10.1101/2023.03.27.534416, doi:10.1101/2023.03.27.534416. This article has 0 citations.
(zhou2023dynamicsofthe pages 11-15): Rui Zhou, Michelle L. Swift, Aleem Syed, Kaimeng Huang, Lisa Moreau, John A. Tainer, Panagiotis A. Konstantinopoulos, Alan D. D’Andrea, Yizhou Joseph He, and Dipanjan Chowdhury. Dynamics of the dynll1/mre11 complex regulates dna end resection and recruitment of the shieldin complex to dsbs. bioRxiv, Mar 2023. URL: https://doi.org/10.1101/2023.03.27.534416, doi:10.1101/2023.03.27.534416. This article has 0 citations.
(zhou2023dynamicsofthe pages 25-27): Rui Zhou, Michelle L. Swift, Aleem Syed, Kaimeng Huang, Lisa Moreau, John A. Tainer, Panagiotis A. Konstantinopoulos, Alan D. D’Andrea, Yizhou Joseph He, and Dipanjan Chowdhury. Dynamics of the dynll1/mre11 complex regulates dna end resection and recruitment of the shieldin complex to dsbs. bioRxiv, Mar 2023. URL: https://doi.org/10.1101/2023.03.27.534416, doi:10.1101/2023.03.27.534416. This article has 0 citations.
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