Functional Divergence of Fanconi Anemia Genes

Abstract

The Fanconi anemia (FA) pathway is a major mechanism countering DNA interstrand crosslinking lesions. Deficiencies in FA leads to DNA damage sensitivity and profound cancer predisposition. The DNA remodeling enzyme FANCM and its DNA‐binding partner, FAAP24, constitute a complex involved in activation of FA pathway, but neither gene has distinct patient mutants. We created isogenic models for both FANCM and FAAP24 and investigated their integrated functions in DNA damage response. We found that FANCM and FAAP24 coordinately facilitate FA pathway activation and suppress sister chromatid exchange. Importantly, we show that FANCM and FAAP24 possess non‐overlapping functions such that FAAP24 promotes ATR‐mediated checkpoint activation particularly in response to DNA crosslinking agents, whereas FANCM participates in recombination‐independent interstrand crosslink repair by facilitating recruitment of lesion incision activities which requires it translocase activity. Our results suggest divergent roles played by FANCM and FAAP24 in maintaining genomic integrity.