Table 2. Genes associated with ICL sensitivity.
| Gene | Disease | Cancer types | Functions of gene product |
|---|---|---|---|
|
FANCA, FANCG, FANCF, FANCC, FANCE and FANCB |
FA | AML and HNSCC | Forms the FA core complex that is required to activate FANCL |
| FANCL | FA | None reported (FANCL mutations account for only two cases of FA) |
Ubiquitin ligase that monoubiquitylates FANCD2–FANCI |
| FANCD2 and FANCI | FA | AML and HNSCC | Binds DNA, promotes DNA damage signalling and the recruitment of repair enzymes |
|
USP1 and WDR48 (which encodes UAF1) |
Heterodimer required for the deubiquitylation of FANCD2 and the completion of ICL repair |
||
| BRIP1 (which encodes FANCJ) | FA | AML and breast* cancer | 3′-5′ DNA helicase with preference for branched DNA substrates |
| FAN1 | DNA 5′-3′ exonuclease, and 5′-flap endonuclease. Specifically binds the monoubiquitylated form of FANCD2 |
||
|
REV1, DNA polymerase ν and DNA polymerase ζ |
Translesion synthesis polymerases that are required for DNA synthesis at the site of ICLs |
||
| HELQ | Helicase function required for the completion of ICL repair | ||
| FANCM | FA | None reported (only two cases of FA with FANCM mutations) |
5′-3′ translocase and branch migration activity. Structure-specific DNA junction binding and recruitment of FA core complex and BLM. Checkpoint activation |
|
APITD1 (which encodes MHF1), STRA13 (which encodes MHF2) and C19orf40 (which encodes FAAP24) |
FANCM accessory factors | ||
| PALB2 (which encodes FANCN) | FA and BOC |
AML, medulloblastoma, neuroblastoma, breast and ovarian* cancer and pancreatic* cancer |
Stabilizes and promotes localization of BRCA2 to DNA damage sites |
| BRCA2 (which encodes FANCD1) | FA and BOC |
AML, ALL, medulloblastoma, breast and ovarian* cancer and prostate* cancer |
Required for loading of RAD51 recombinase onto DNA |
| BRCA1 | BOC | Breast and ovarian* cancer | Ubiquitin ligase activity towards histone H2A and CTIP |
| SLX4 (which encodes FANCP)–SLX1 | FA | HNSCC (one case reported) | Structure-specific endonuclease |
| ERCC4 (which encodes XPF)–ERCC1 | XP and XFE |
Skin cancer, HNSCC* and lung cancer* |
DNA 5′-flap endonuclease |
| MUS81-EME1 | DNA 3′-flap endonuclease | ||
| RAD51 | Recombinase that searches for homology in DNA templates and promotes strand exchange |
||
| RAD51C (which encodes FANCO) | FA and BOC |
None reported (four cases of FA with RAD51C mutations), breast and ovarian cancer* |
Required for HR |
| NBS1 | NBS | B cell lymphoma | Required for HR. Component of the MRE11-RAD50-NBS1 (MRN) complex |
| BLM | BS | A broad range of cancers are increased |
5′-3′ DNA helicase, inhibits RAD51 strand invasion and promotes dissolution of Holliday junction intermediates |
|
TOP3A, RMI1 and C16orf75 (which encodes RMI2) |
Required for Holliday junction resolution by BLM | ||
| ATR | SS | None reported | Senses accumulation of RPA-coated ssDNA. It is a kinase and phosphorylates many targets that are required to activate cell cycle checkpoints and promote repair |
ALL, acute lymphocytic leukaemia; AML, acute myeloid leukaemia; APITD1, apoptosis-inducing, TAF9-like domain 1; ATR, ataxia-telangiectasia and Rad3-related; BLM, Bloom’s syndrome RecQ-helicase like; BOC, breast and ovarian cancer susceptibility; BRIP1, BRCA1-interacting protein 1; BS, Bloom’s syndrome; FA, Fanconi anaemia; FAN1, Fanconi-associated nuclease 1; HELQ, helicase, POLQ-like; HNSCC, head and neck squamous cell carcinoma; HR, homologous recombination; ICL, interstrand crosslink; NBS, Nijmegen breakage syndrome; NBS1, nibrin; PALB2, partner and localizer of BRCA2; RMI, RecQ-mediated genome instability; SS, Seckel syndrome; ssDNA, single-stranded DNA; STRA13, stimulated by retinoic acid 13; TOP3A, topoisomerase IIIα; XFE, XPF/ERCC1 progeroid syndrome; UAF1, USP1-associated factor 1; USP1, ubiquitin specific peptidase 1; WDR48, WD repeat domain 48; XP, xeroderma pigmentosum.
Documented in heterozygotes only.