FANCM (Q8IYD8) gene review notes

Human Fanconi anemia group M protein. 2048 aa, ~250 kDa. HGNC:23168, chr14. DEAH-box
helicase family, FANCM sub-subfamily. Ortholog of archaeal Hef, S. pombe Fml1, S. cerevisiae Mph1.

Domain architecture (UniProt Q8IYD8)

• N-terminal helicase ATP-binding (DEAH/SF2) domain ~98-266; Walker A ATP-binding 111-118; DEAH box 214-217 (K117 catalytic).
• Helicase C-terminal domain ~452-627.
• CENPS/CENPX (MHF) interaction region ~661-800.
• C-terminal ERCC4/XPF-like (nuclease-dead) + (HhH)2 domain; FAAP24 interaction region ~1727-2048.
• Large intrinsically disordered central/C-terminal regions.

Core biology

FANCM is a DNA-dependent ATPase / ATP-dependent DNA translocase that anchors the FA core complex
to chromatin at stalled replication forks and DNA interstrand crosslinks (ICLs). Its N-terminal
translocase catalyzes ATP-dependent branch migration of forks and Holliday junctions (fork
remodeling); its nuclease-dead C-terminal ERCC4-like domain heterodimerizes with FAAP24, and it
binds the MHF1/MHF2 (CENPS/CENPX) histone-fold complex. Required for efficient FANCD2
monoubiquitination, ATR checkpoint signaling, replication traverse of ICLs, and suppression of
sister-chromatid exchange / crossover recombination.

Provenance quotes

Catalytic/translocase engine:
- PMID:16116422
- PMID:16116422
- PMID:16116422
- Human FANCM is a translocase, not a canonical duplex-unwinding helicase: PMID:19423727
- ATPase required for cross-linker resistance / fork remodeling but not for FANCD2 monoub: PMID:19423727
- Branch migration of fork/HJ: PMID:20347429
- PMID:20347429
- ATP dependence of branch migration: PMID:20347429 and K117R abolishes it: PMID:20347429

Recruitment / chromatin anchoring / FA pathway:
- PMID:19423727
- PMID:19423727
- PMID:17289582
- PMID:17289582
- PMID:17289582
- FANCM chromatin-restricted: PMID:20347429

MHF complex / DNA binding / fork remodeling stimulation:
- PMID:20347428
- PMID:20347428
- PMID:20347428
- MHF1/MHF2 = CENPS/CENPX: PMID:20347429
- MHF is core complex component: PMID:20347429
- PMID:20347429

FA core complex membership (BRAFT supercomplex):
- UniProt SUBUNIT: FA core complex = CENPS, CENPX, FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, FANCM, FAAP24, FAAP100; associates with BLM complex to form BRAFT.

ICL repair / checkpoint:
- PMID:20347429
- FANCD2 monoub required: PMID:29231814
- Checkpoint proficiency preserved in patient cells: PMID:29231814

HR regulation (not core HR): FANCM not essential for HR/RAD51 foci:
- PMID:19423727
- Crossover/SCE suppression: PMID:19423727

Meiotic / germ cell expression (POF15, SPGF28):
- PMID:29231814
- Truncation removes C-terminal endonuclease + FAAP24 domain: PMID:29231814

Replisome / replication timing:
- PMID:32769987

Annotation-specific judgments

• RNA helicase activity (GO:0003724, IEA from EC:3.6.4.13): legacy alt-name "ATP-dependent RNA helicase";
  functionally FANCM is a DNA-dependent ATPase / DNA translocase — no RNA helicase activity demonstrated.
  EC→GO over-mapping; REMOVE.
• 3'-5' DNA helicase activity (GO:0043138, IBA+IEA): human FANCM shows translocase/branch-migration,
  not canonical processive duplex unwinding ("only translocase activity was observed", PMID:19423727).
  MODIFY -> DNA translocase activity (GO:0015616).
• protein binding (GO:0005515, 7 IPI incl. FAAP24, CENPS, MCM2, TRIM27, EPN2 + interactome maps):
  uninformative; MARK_AS_OVER_ANNOTATED (specific interactions captured via complex/MHF terms).
• cytosol (GO:0005829, TAS Reactome PKR pathway): FANCM is nuclear/chromatin-restricted; peripheral
  PKR-signaling annotation; MARK_AS_OVER_ANNOTATED.
• resolution of meiotic recombination intermediates (GO:0000712, IMP 20347428) and homologous
  recombination (GO:0035825, IEA): genuine but regulatory/non-core (FANCM limits crossovers/SCE;
  not essential for RAD51-dependent HR). KEEP_AS_NON_CORE.