Rescue of Stalled Replication Forks by the DNA Translocase FANCM

Abstract

Fanconi anemia (FA) is a chromosomal instability syndrome that manifests with congenital abnormalities, bone marrow failure and cancer predisposition. To date, fourteen FA genes have been identified and implicated in a ubiquitin signaling pathway, in S phase checkpoint activation, in lesion bypass and in DNA double‐strand break (DSB) repair by homologous recombination.FANCM is a DNA translocase that acts as a molecular scaffold involved in multiple DNA damage signaling and processing reactions. FANCM interacts with : 1) the checkpoint protein HCLK2 to facilitate DNA damage signaling; 2) with the Bloom's complex at stalled forks; 3) and with the FA ubiquitin ligase complex, promoting its recruitment to chromatin and the monoubiquitination of FANCD2 and FANCI.Our biochemical studies revealed that FANCM binds and translocates the branch point of DNA structures that mimic replication and repair intermediates, suggesting that FANCM may remodel replication intermediates to promote recovery. Using a molecular combing approach, we have observed that FANCM facilitates the restart of replication forks stalled by DNA topoisomerase I inhibitors. Our recent efforts have focused on studying the role new DNA damage response proteins that interact with FANCM.Research support: ARC Association pour la Recherche sur le Cancer, ANR Agence Nationale de la Recherche, SNSF Swiss National Science Foundation.