title: Opposing ISWI- and CHD-class chromatin remodeling activities orchestrate heterochromatic DNA repair.
abstract: Heterochromatin is a barrier to DNA repair that correlates strongly with elevated somatic mutation in cancer. CHD class II nucleosome remodeling activity (specifically CHD3.1) retained by KAP-1 increases heterochromatin compaction and impedes DNA double-strand break (DSB) repair requiring Artemis. This obstruction is alleviated by chromatin relaxation via ATM-dependent KAP-1S824 phosphorylation (pKAP-1) and CHD3.1 dispersal from heterochromatic DSBs; however, how heterochromatin compaction is actually adjusted after CHD3.1 dispersal is unknown. In this paper, we demonstrate that Artemis-dependent DSB repair in heterochromatin requires ISWI (imitation switch)-class ACF1-SNF2H nucleosome remodeling. Compacted chromatin generated by CHD3.1 after DNA replication necessitates ACF1-SNF2H-mediated relaxation for DSB repair. ACF1-SNF2H requires RNF20 to bind heterochromatic DSBs, underlies RNF20-mediated chromatin relaxation, and functions downstream of pKAP-1-mediated CHD3.1 dispersal to enable DSB repair. CHD3.1 and ACF1-SNF2H display counteractive activities but similar histone affinities (via the plant homeodomains of CHD3.1 and ACF1), which we suggest necessitates a two-step dispersal and recruitment system regulating these opposing chromatin remodeling activities during DSB repair.
authors.affiliation: Robson DNA Science Centre, Southern Alberta Cancer Research Institute; and Department of Biochemistry and Molecular Biology and Department of Oncology, Cumming School of Medicine; University of Calgary, Calgary, Alberta T2N 4N1, Canada Robson DNA Science Centre, Southern Alberta Cancer Research Institute; and Department of Biochemistry and Molecular Biology and Department of Oncology, Cumming School of Medicine; University of Calgary, Calgary, Alberta T2N 4N1, Canada Robson DNA Science Centre, Southern Alberta Cancer Research Institute; and Department of Biochemistry and Molecular Biology and Department of Oncology, Cumming School of Medicine; University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Karolin
authors.initials: K
authors.lastname: Klement
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, 2333 ZC Leiden, Netherlands.
authors.forename: Martijn S
authors.initials: MS
authors.lastname: Luijsterburg
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
authors.forename: Jordan B
authors.initials: JB
authors.lastname: Pinder
authors.affiliation: Robson DNA Science Centre, Southern Alberta Cancer Research Institute; and Department of Biochemistry and Molecular Biology and Department of Oncology, Cumming School of Medicine; University of Calgary, Calgary, Alberta T2N 4N1, Canada Robson DNA Science Centre, Southern Alberta Cancer Research Institute; and Department of Biochemistry and Molecular Biology and Department of Oncology, Cumming School of Medicine; University of Calgary, Calgary, Alberta T2N 4N1, Canada Robson DNA Science Centre, Southern Alberta Cancer Research Institute; and Department of Biochemistry and Molecular Biology and Department of Oncology, Cumming School of Medicine; University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Chad S
authors.initials: CS
authors.lastname: Cena
authors.affiliation: Robson DNA Science Centre, Southern Alberta Cancer Research Institute; and Department of Biochemistry and Molecular Biology and Department of Oncology, Cumming School of Medicine; University of Calgary, Calgary, Alberta T2N 4N1, Canada Robson DNA Science Centre, Southern Alberta Cancer Research Institute; and Department of Biochemistry and Molecular Biology and Department of Oncology, Cumming School of Medicine; University of Calgary, Calgary, Alberta T2N 4N1, Canada Robson DNA Science Centre, Southern Alberta Cancer Research Institute; and Department of Biochemistry and Molecular Biology and Department of Oncology, Cumming School of Medicine; University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Victor
authors.initials: V
authors.lastname: Del Nero
authors.affiliation: Robson DNA Science Centre, Southern Alberta Cancer Research Institute; and Department of Biochemistry and Molecular Biology and Department of Oncology, Cumming School of Medicine; University of Calgary, Calgary, Alberta T2N 4N1, Canada Robson DNA Science Centre, Southern Alberta Cancer Research Institute; and Department of Biochemistry and Molecular Biology and Department of Oncology, Cumming School of Medicine; University of Calgary, Calgary, Alberta T2N 4N1, Canada Robson DNA Science Centre, Southern Alberta Cancer Research Institute; and Department of Biochemistry and Molecular Biology and Department of Oncology, Cumming School of Medicine; University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Wintersinger
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
authors.forename: Graham
authors.initials: G
authors.lastname: Dellaire
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, 2333 ZC Leiden, Netherlands.
authors.forename: Haico
authors.initials: H
authors.lastname: van Attikum
authors.affiliation: Robson DNA Science Centre, Southern Alberta Cancer Research Institute; and Department of Biochemistry and Molecular Biology and Department of Oncology, Cumming School of Medicine; University of Calgary, Calgary, Alberta T2N 4N1, Canada Robson DNA Science Centre, Southern Alberta Cancer Research Institute; and Department of Biochemistry and Molecular Biology and Department of Oncology, Cumming School of Medicine; University of Calgary, Calgary, Alberta T2N 4N1, Canada Robson DNA Science Centre, Southern Alberta Cancer Research Institute; and Department of Biochemistry and Molecular Biology and Department of Oncology, Cumming School of Medicine; University of Calgary, Calgary, Alberta T2N 4N1, Canada A.Goodarzi@ucalgary.ca.
authors.forename: Aaron A
authors.initials: AA
authors.lastname: Goodarzi
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D004265:DNA Helicases / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004720:Endonucleases; D006570:Heterochromatin / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000378:metabolism; D009707:Nucleosomes / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D014157:Transcription Factors / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
chemical_list: D000251:Adenosine Triphosphatases; D064007:Ataxia Telangiectasia Mutated Proteins; D002868:Chromosomal Proteins, Non-Histone; D004265:DNA Helicases; D004268:DNA-Binding Proteins; D004720:Endonucleases; D006570:Heterochromatin; D006657:Histones; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D009687:Nuclear Proteins; D009707:Nucleosomes; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; C492319:BAZ1A protein, human; D000092468:Bromodomain Containing Proteins; C506646:RNF20 protein, human; C576324:ATM protein, human; C426344:DCLRE1C protein, human; C409462:SMARCA5 protein, human; C115322:CHD3 protein, human