Structural basis of Fanconi Anemia pathway activation by FANCM

ABSTRACT: FANCM is crucial in genome maintenance, functioning in the Fanconi anemia (FA) pathway, alternative lengthening of telomeres (ALT), and replication-fork protection. FANCM recognizes branched DNA structures and promotes their remodeling through ATP-dependent branch migration. The protein has emerged as a promising therapeutic target due to synthetic lethal-interactions with BRCA1, SMARCAL1, and RAD52, and in ALT-positive cancers. Here we present crystal structures of FANCM's N-terminal ATP-dependent translocase domain (2.2Å) and C-terminal FAAP24-bound region (2.4Å), both complexed with branched DNA. Through structural analysis, biochemical reconstitution, and cellular studies, we demonstrate that FANCM employs two distinct mechanisms: an ATP-dependent branch-migration activity essential fo

SUBMITTER: Rohan Bythell-Douglas 

PROVIDER: S-SCDT-10_1038-S44318-025-00468-3 | biostudies-other |

REPOSITORIES: biostudies-other