Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins

Abstract

Fanconi anaemia (FA) is a rare genetic disease featuring bone marrow failure, various developmental abnormalities, genomic instability, cancer predisposition and cellular hypersensitivity to DNA-crosslinking drugs. FA has been considered as a useful model to study the pathway that repairs interstrand DNA crosslinks. Three FA genes are identical to breast cancer susceptibility (BRCA) genes. FA and BRCA gene products function in a novel DNA-damage response network. Thirteen FA genes have been identified to date. They can be classified into three groups, each of which acts at a different stage in the FA–BRCA DNA-damage response network. Group I consists of eight FA proteins (FANCA, B, C, E, F, G, L and M). They form the FA core complex, together with FANCA-associated polypeptides FAAP100 and FAAP24. The core complex monoubiquitylates the ID complex in response to DNA damage, and might also participate in DNA repair through the DNA-processing activities of FANCM–FAAP24. Group II consists of FANCD2 and FANCI, which form the FA–ID complex. In response to DNA damage, The ID complex becomes monoubiquitylated, leading to its redistribution to sites of DNA damage where it colocalizes with BRCA1 and γH2AX, a histone H2A variant. These proteins are essential for the redistribution of the ID complex. Group III proteins include FANCD1 (or BRCA2), FANCN(or partner and localizer of BRCA2 (PALB2)), and FANCJ (also known as BRCA1-interacting protein 1 (BRIP1) or BRCA1-associated C-terminal helicase 1 (BACH1)), which are all products of breast cancer susceptibility genes. BRCA2 and PALB2 form a complex with RAD51 recombinase and BRCA1, and this complex mediates homologous recombination-dependent repair of DNA damage. FANCJ is a DNA helicase, which forms a distinct complex with BRCA1, mutL homologue 1(MLH1) and post-meiotic segregation increased 2 (PMS2). FA proteins crosstalk with many molecules that are known to be involved in the DNA-damage response. These include homologous recombination protein RAD51 and translesion polymerases REV1 and REV3. The checkpoint kinase ataxia telangiectasia and Rad3-related protein (ATR) acts upstream of the FA–BRCA network. The Bloom syndrome helicase (BLM) and its partners form a large, stable complex with the FA core complex.