| Claim/Function | Evidence type | Key details/quantitative data | Source (authors, year) | DOI URL |
|---|---|---|---|---|
| **Identity/orthology: C. elegans fan-1 = C01G5.8 / UniProt P90740, a FAN1-family nuclease** | Primary biochemistry/orthology; worm-relevant family mapping | MacKay et al. explicitly include **C. elegans P90740** in the FAN1 ortholog schematic and identify FAN1 proteins as conserved DNA-repair nucleases; domain schematic shows **UBZ**, **SAP**, and **VRR_nuc** domains across orthologs, supporting assignment of worm **fan-1/C01G5.8** to the FAN1 family (pqac-00000014, pqac-00000028) | MacKay et al., 2010 | https://doi.org/10.1016/j.cell.2010.06.021 |
| **Catalytic core and domain logic of FAN1 family** | Primary biochemistry; review | Human FAN1 contains **UBZ-type ubiquitin-binding**, **SAP-type DNA-binding**, and **VRR_nuc/DUF994** nuclease domains; VRR_nuc bears a **PD-(D/E)XK** nuclease motif. A 2023 synthesis further describes a bi-lobed architecture with N-terminal helical/SAP region and C-terminal **TPR + VRR nuclease** region, supporting inference that worm FAN-1 is a structure-specific phosphodiesterase acting on branched DNA (pqac-00000015, pqac-00000017, pqac-00000022) | MacKay et al., 2010; Ouanounou, 2023 | https://doi.org/10.1016/j.cell.2010.06.021 |
| **Primary biochemical function: structure-specific nuclease with 5′-flap preference** | Primary biochemistry | Recombinant FAN1 shows strong endonuclease activity on **5′ flap** substrates and weaker activity on replication-fork-like DNA; cleavage occurs on the flap-containing strand ~**4 nt** from the branchpoint. Reported observed cleavage rates were **>0.2 s⁻¹** for WT FAN1 versus **0.0003 s⁻¹** for the catalytic DR mutant, supporting a direct catalytic role of the conserved nuclease domain (pqac-00000020, pqac-00000023) | MacKay et al., 2010 | https://doi.org/10.1016/j.cell.2010.06.021 |
| **Broader substrate specificity of FAN1 family relevant to worm annotation** | Review/biochemical synthesis | FAN1 processes branched and lesion-containing DNA including **5′ flaps, replication forks, dsDNA, bubbles/D-loops, nicks, gaps, and ICL substrates**; activity is favored on branched/double-flap structures and influenced by **5′-terminal phosphate**, flap length, and metal ions. These family-level properties are the strongest biochemical basis for inferring worm substrate scope where direct worm enzymology is limited (pqac-00000016, pqac-00000017, pqac-00000022) | Ouanounou, 2023 | N/A in retrieved context |
| **Ce-fan-1 protects worms from DNA interstrand crosslink (ICL) damage** | Worm genetics | In C. elegans, deletion/RNAi of **Ce-fan-1 (C01G5.8)** confers hypersensitivity to **nitrogen mustard (HN2)** and **cisplatin**; L1 larvae show impaired progression after ICL exposure, while mutants have **no overt developmental defects without challenge**. MacKay et al. note Ce-fan-1 mutants can be **more sensitive than fcd-2/FANCD2-ortholog mutants** under ICL stress (pqac-00000000, pqac-00000006) | MacKay et al., 2010 | https://doi.org/10.1016/j.cell.2010.06.021 |
| **ICL sensitivity is accompanied by developmental and germline defects after TMP/UVA in worms** | Worm genetics/phenotyping | After **TMP/UVA** crosslinking treatment, **fan-1** mutants show WT-like mitotic features but **no or a disorganized, non-functional germline**, leading to **sterility**; phenotype was described as slightly worse than **slx-1** mutants. fan-1 animals also show increased propensity for **protruding vulva** after treatment (pqac-00000005, pqac-00000013) | Wilson et al., 2017 | https://doi.org/10.1093/nar/gkx660 |
| **FAN-1 is recruited to the nucleoplasm after crosslinks in an UNC-84-dependent manner** | Worm localization/genetics | FAN-1 is **not efficiently recruited to the nucleoplasm in the absence of UNC-84**; however, FAN-1 nuclear localization does **not** require an intact LINC complex generally, suggesting **UNC-84 acts as a tether**. In **zyg-12** mutants, FAN-1::GFP localization was reported as similar to WT, consistent with UNC-84 being the critical factor for recruitment (pqac-00000024, pqac-00000025) | Lawrence et al., 2016 | https://doi.org/10.1083/jcb.201604112 |
| **Pathway placement: FAN-1 acts with FA-linked components but is not a classic FA core gene** | Worm genetics/localization; review | FAN-1 is linked to the Fanconi pathway via FANCD2 interactions and ICL repair, but multiple sources note it is **not a classic FA gene**. In worms, UNC-84/LINC biology suggests FAN-1 function must be coordinated with **NHEJ inhibition** and **HR promotion** to avoid unproductive repair at crosslinks (pqac-00000008, pqac-00000025, pqac-00000021) | Lawrence et al., 2016; Ouanounou, 2023 | https://doi.org/10.1083/jcb.201604112 |
| **FNCM-1 recruits FCD-2 and downstream FAN-1 to the germline** | Worm localization/genetics | Kim et al. state explicitly that **C. elegans FNCM-1 is required for recruiting FCD-2 and its downstream nuclease FAN-1 in the germline**; the putative helicase/translocase domain of FNCM-1 is required for this recruitment. FAN-1 also participates in the **dynamic localization pattern** of FA-pathway factors after **HU-induced replication-fork arrest** (pqac-00000010, pqac-00000026, pqac-00000027) | Kim et al., 2018 | https://doi.org/10.1534/genetics.118.300823 |
| **Replication-stress relocalization context for FAN-1** | Worm localization | Under **HU**-induced replication stress, FAN-1 is reported among proteins showing a **dynamic localization pattern** with FNCM-1, FCD-2, and SPR-5. Quantitative localization values in the excerpt were reported for related markers rather than FAN-1 directly; for example, **SPR-5/FNCM-1** colocalization in pachytene increased with **P = 0.0079** (n = 4–6 gonads), supporting a replication-stress-responsive FA-associated compartment in which FAN-1 participates (pqac-00000011, pqac-00000027) | Kim et al., 2018 | https://doi.org/10.1534/genetics.118.300823 |
| **Human-cell repair kinetics reinforce FAN1’s ICL-repair role relevant to worm annotation** | Primary cell biology/biochemistry | In human cells depleted of FAN1, after cisplatin there was **almost no decrease** in the fraction of γ-H2AX-positive cells over time; controls had ~**80%** of cells with **2–40 γ-H2AX foci at 24 h**, whereas by **96 h** **>50%** of FAN1-depleted cells remained γ-H2AX-positive, indicating defective processing/resolution of ICL-associated damage. This supports the same core repair function inferred for worm FAN-1 (pqac-00000006) | MacKay et al., 2010 | https://doi.org/10.1016/j.cell.2010.06.021 |
| **2023 development: PCNA/RFC-dependent activation on repeat-extrusion substrates** | Recent primary biochemistry | FAN1 has a newly emphasized activity on **triplet-repeat extrusions**; **RFC + PCNA + ATP** activate a strand-directed FAN1 reaction near extrahelical repeats. FAN1 cleaves near the extrusion and can remove both short and long repeat extrusions, extending FAN1 function beyond classical ICL repair and suggesting possible conserved crosstalk with replication factors in other organisms, including worms (pqac-00000019, pqac-00000029) | Phadte et al., 2023 | https://doi.org/10.1073/pnas.2302103120 |
| **Quantitative 2023 mechanistic details for PCNA-dependent FAN1 activation** | Recent primary biochemistry | On small repeat extrusions, FAN1 generated a hydrolytic product of ~**10 nt** with the cut located ~**14 nt** from the extrusion. FAN1 activity dropped by **>3-fold** when KCl increased from **70 mM to 115 mM**, but **PCNA restored activity** under higher salt. In some assays RFC was not further stimulatory, whereas PCNA-dependent complex formation required the correct strand orientation, refining how PCNA controls FAN1 substrate engagement (pqac-00000030) | Phadte et al., 2023 | https://doi.org/10.1073/pnas.2302103120 |
| **2023 development: FA-dependent and FA-independent recruitment modes** | Recent review/synthesis | Ouanounou summarizes evidence that FAN1 recruitment via **UBZ binding to monoubiquitinated ID2 (FANCD2/FANCI)** is important, but **UBZ-mutant FAN1 can still rescue ICL repair** in some mammalian systems. This is relevant for C. elegans because worms lack parts of the canonical FA core machinery, so FAN-1 may retain function through partially FA-independent recruitment/activation routes (pqac-00000021, pqac-00000031, pqac-00000034) | Ouanounou, 2023 | N/A in retrieved context |
| **2024 worm-specific mechanistic advance: FAN-1 promotes TLS at psoralen ICLs** | Recent worm genetics/mechanism | In a defined psoralen-ICL assay, **fan-1** mutants showed an aberrant repair profile in which **wild-type and SNV outcomes were largely absent**, resembling **polh-1, rev-1, rev-3** TLS polymerase mutants. Authors infer that FAN-1 promotes **translesion synthesis (TLS)**, likely by incision/unhooking that creates substrates for TLS polymerases (pqac-00000002, pqac-00000007, pqac-00000036) | Tijsterman et al., 2024 (preprint) | https://doi.org/10.21203/rs.3.rs-3898201/v1 |
| **2024 worm-specific mechanistic advance: FAN-1 suppresses POLQ/HELQ-mediated end joining** | Recent worm genetics/mechanism | The 2024 preprint proposes a dual role for FAN-1 in psoralen ICL repair: enabling **TLS** while suppressing **POLQ/HELQ-mediated end joining (TMEJ)**. Loss of fan-1 increases TMEJ-type deletions after UV-TMP treatment, arguing that FAN-1 helps channel repair away from deletion-prone end joining and toward productive bypass (pqac-00000032, pqac-00000036) | Tijsterman et al., 2024 (preprint) | https://doi.org/10.21203/rs.3.rs-3898201/v1 |
| **Expert-level annotation takeaway for C. elegans fan-1** | Integrated inference from worm genetics + family biochemistry | The best-supported annotation is that **fan-1/P90740** encodes a **structure-specific DNA nuclease** acting mainly during **interstrand crosslink repair** and **replication-associated DNA damage processing**, likely via incision/unhooking of branched/5′-flap-like intermediates; it acts in FA-linked but partly parallel pathways, is recruited in the germline by **FNCM-1/FCD-2**, and is relocalized to the nucleoplasm by **UNC-84** after crosslinks. Recent work extends likely function to pathway-choice control and potentially PCNA-coupled processing of non-B DNA intermediates (pqac-00000000, pqac-00000010, pqac-00000025, pqac-00000029, pqac-00000036) | Integrated from MacKay et al., 2010; Lawrence et al., 2016; Kim et al., 2018; Phadte et al., 2023; Tijsterman et al., 2024 | https://doi.org/10.1016/j.cell.2010.06.021; https://doi.org/10.1083/jcb.201604112; https://doi.org/10.1534/genetics.118.300823; https://doi.org/10.1073/pnas.2302103120; https://doi.org/10.21203/rs.3.rs-3898201/v1 |


*Table: This table summarizes the strongest evidence supporting functional annotation of C. elegans fan-1/P90740, integrating worm genetics, localization studies, core FAN1 biochemistry, and 2023-2024 mechanistic developments. It is useful as a compact evidence map linking claims about function, pathway placement, localization, and substrate specificity to specific sources and quantitative details.*