MHF1-MHF2, a Histone-Fold-Containing Protein Complex, Participates in the Fanconi Anemia Pathway via FANCM

Abstract

SUMMARY FANCM is a Fanconi anemia nuclear core complex protein required for the functional integrity of the FANC-BRCA pathway of DNA damage response and repair. Here we report the isolation and characterization of two histone-fold-containing FANCM-associated proteins, MHF1 and MHF2. We show that suppression of MHF1 expression results in 1) destabilization of FANCM and MHF2, 2) impairment of DNA damage-induced monoubiquitination and foci formation of FANCD2, 3) defective chromatin localization of FA nuclear core complex proteins, 4) elevated MMC-induced chromosome aberrations, and 5) sensitivity to MMC and camptothecin. We also provide biochemical evidence that MHF1 and MHF2 assemble into a heterodimer that binds DNA and enhances the DNA branch migration activity of FANCM. These findings reveal critical roles of the MHF1-MHF2 dimer in DNA damage repair and genome maintenance through FANCM.

Defining the molecular interface that connects the Fanconi anemia protein FANCM to the Bloom syndrome dissolvasome

“…1F). FANCM could act to remodel the replication fork, possibly in coordination with BLM and Top3α (20)(21)(22)(23)(24). Furthermore, FANCM interacts with a large number of proteins that mediate many DNA-repair pathways.…”

Stepwise unfolding supports a subunit model for vertebrate kinetochores

“…CENP-S/MHF1 has a role in the resolution of DNA interstrand crosslinks and sister chromatid exchanges (SCEs) by the Fanconi Anemia complex. CENP-S is required for chromatin targeting and stability of the FANCM subcomplex, of which it is a member together with CENP-X/MHF2 (39,40). In DT40 cells, SCEs increased 3-4-fold when CENP-S/MHF1 was depleted (39,40).…”

“…CENP-S is required for chromatin targeting and stability of the FANCM subcomplex, of which it is a member together with CENP-X/MHF2 (39,40). In DT40 cells, SCEs increased 3-4-fold when CENP-S/MHF1 was depleted (39,40). Thus, CENP-S involvement in centrochromatin stability may reflect a more general role in chromatin higher order structure across the cell cycle.…”

Multiple Interactions of the Intrinsically Disordered Region between the Helicase and Nuclease Domains of the Archaeal Hef Protein

“…Therefore, the proper function of FANCM is responsible for preventing both Fanconi anemia and Bloom's syndrome. In addition, two histone-fold containing proteins, MHF1 and MHF2, which were recently identified as FANCM-associated factors, form the stable complex MHF1-MHF2 and stimulate the DNA-binding activity of FANCM (47,48). The stable association with FANCM and the DNA-binding activity of MHF activate the FA repair pathway.…”