Abstract
FANCM is a Fanconi anemia nuclear core complex protein required for the functional integrity of the FA‐BRCA pathway of DNA damage response and repair. FANCM is a highly conserved protein that belongs to the SF2 superfamily of helicases/translocases. Previously, we have reported the isolation and characterization of two novel histone‐fold‐containing FANCM‐associated proteins, MHF1 and MHF2. These proteins form a complex that is important for DNA damage‐induced monoubiquitination and foci formation of FANCD2, as well as chromatin localization of FA nuclear core complex proteins. Depletion of MHF complex resulted in elevated MMC‐induced chromosome aberrations, and sensitivity of cells to MMC and camptothecin. Biochemical characterization of the MHF complex showed that it assembles into a heterodimer that binds double stranded DNA and most importantly enhances the DNA branch migration activity of FANCM. We have carried out structural work to characterize the MHF complex by X‐ray crystallography. Based on the high resolution crystal structure of the MHF complex we have designed and tested mutants of MHF complex that are defective in DNA binding and FANCM interaction and showed that both protein‐protein interactions and DNA binding of MHF complex are needed for stimulation of FANCM activity.
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