The structure of the FAnCm–mHF complexreveals physical features for functional assembly

摘要

Fanconi anaemia is a rare genetic disease characterized by chromosomal instability and cancersusceptibility. The Fanconi anaemia complementation group protein m (FAnCm) forms anevolutionarily conserved DnA-processing complex with mHF1/mHF2 (histone-fold-containingproteins), which is essential for DnA repair in response to genotoxic stress. Here we presentthe crystal structures of the mHF1–mHF2 complex alone and bound to a fragment of FAnCm(FAnCm661-800, designated FAnCm-F). The structures show that mHF1 and mHF2 form acompact tetramer to which FAnCm-F binds through a ‘dual-V’ shaped structure. FAnCm-Fand (mHF1–mHF2)2 cooperate to constitute a new DnA-binding site that is coupled to thecanonical L1L2 region. Perturbation of the mHF–FAnCm-F structural plasticity changes thelocalization of FAnCm in vivo. The mHF–FAnCm interaction and its subcellular localizationare altered by a disease-associated mutant of FAnCm. These findings reveal the molecularbasis of mHF–FAnCm recognition and provide mechanistic insights into the pathway leadingto Fanconi anaemia.