ATM is a central regulator of the cellular responses to DNA double-strand breaks (DSBs). Here we identify a biochemical interaction between ATM and RSF1 and we characterise the role of RSF1 in this response. The ATM–RSF1 interaction is dependent upon both DSBs and ATM kinase activity. Together with SNF2H/SMARCA5, RSF1 forms the RSF chromatin-remodelling complex. Although RSF1 is specific to the RSF complex, SNF2H/SMARCA5 is a catalytic subunit of several other chromatin-remodelling complexes. Although not required for checkpoint signalling, RSF1 is required for efficient repair of DSBs via both end-joining and homology-directed repair. Specifically, the ATM-dependent recruitment to sites of DSBs of the histone fold proteins CENPS/MHF1 and CENPX/MHF2, previously identified at centromeres, is RSF1-dependent. In turn these proteins recruit and regulate the mono-ubiquitination of the Fanconi Anaemia proteins FANCD2 and FANCI. We propose that by depositing CENPS/MHF1 and CENPX/MHF2, the RSF complex either directly or indirectly contributes to the reorganisation of chromatin around DSBs that is required for efficient DNA repair.
DNA carries all the information necessary for life; thus damage or loss of genetic material can result in cell death or cancer. The worst-case insult to genetic information is a DNA double-strand break, caused by agents either within the cell (e.g., by-products of respiration, errors of DNA replication) or from outside (e.g., ionizing radiation). Ataxia telangiectasia kinase (ATM) and the Fanconi anaemia proteins perform housekeeping roles in the cell, recognising aberrant DNA structures and promoting their repair. Mutations that affect these proteins are responsible for the eponymous genetic syndromes that are characterised by elevated mutation rate, increased cancer risk, developmental defects, and shortened life span. In this work we identify and characterise a novel link between these two central players in the DNA damage response. We show that the Remodelling and Spacing Factor 1 (RSF1) protein, which can reorganise the compaction of DNA to allow access for other proteins, requires ATM for its function after DNA damage. Specifically, RSF1 recruits two centromeric histone-like proteins that in turn promote mono-ubiquitination and recruitment to sites of damage of FANCD2 and FANCI—two proteins that belong to the Fanconi anaemia pathway. Absence of RSF1 results in defective repair of double-strand DNA breaks, prolonged arrest of the cell cycle, and cell death. Our study suggests that ATM-dependent regulation of the RSF chromatin-remodelling complex is necessary during double-strand break repair to recruit centromeric histones and then Fanconi anaemia proteins.