Abstract
Author SummaryDNA 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.
Highlights
DNA damage can result in mutations leading to either cell death or cancer, and multiple repair pathways exist that are specific to distinct DNA lesions [1,2]
DNA double-strand breaks (DSBs) are toxic lesions repaired by two major pathways, termed homologous recombination (HR) or nonhomologous end joining (NHEJ), that utilise either homology-dependent or -independent mechanisms
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
Summary
DNA damage can result in mutations leading to either cell death or cancer, and multiple repair pathways exist that are specific to distinct DNA lesions [1,2]. DNA double-strand breaks (DSBs) are toxic lesions repaired by two major pathways, termed homologous recombination (HR) or nonhomologous end joining (NHEJ), that utilise either homology-dependent or -independent mechanisms. Additional biological responses to DNA damage include altered transcriptional programmes, transient cell cycle delays termed checkpoints, apoptosis, and senescence. These responses are termed the DNA damage response (DDR). Ataxia telangiectasia, mutated (ATM) and ATM and Rad3related (ATR), a pair of related protein kinases, are central to the DDR [3]. Additional posttranslation modifications, including ubiquitinylation, SUMOylation, poly(ADP-ribosylation), acetylation, and methylation, are required for a successful DDR
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