title: A PALB2-interacting domain in RNF168 couples homologous recombination to DNA break-induced chromatin ubiquitylation.
abstract: DNA double-strand breaks (DSB) elicit a ubiquitylation cascade that controls DNA repair pathway choice. This cascade involves the ubiquitylation of histone H2A by the RNF168 ligase and the subsequent recruitment of RIF1, which suppresses homologous recombination (HR) in G1 cells. The RIF1-dependent suppression is relieved in S/G2 cells, allowing PALB2-driven HR to occur. With the inhibitory impact of RIF1 relieved, it remains unclear how RNF168-induced ubiquitylation influences HR. Here, we uncover that RNF168 links the HR machinery to H2A ubiquitylation in S/G2 cells. We show that PALB2 indirectly recognizes histone ubiquitylation by physically associating with ubiquitin-bound RNF168. This direct interaction is mediated by the newly identified PALB2-interacting domain (PID) in RNF168 and the WD40 domain in PALB2, and drives DNA repair by facilitating the assembly of PALB2-containing HR complexes at DSBs. Our findings demonstrate that RNF168 couples PALB2-dependent HR to H2A ubiquitylation to promote DNA repair and preserve genome integrity.
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Martijn S
authors.initials: MS
authors.lastname: Luijsterburg
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Typas
authors.affiliation: Genome Stability Laboratory, CHU de Québec Research Center, HDQ Pavilion, Oncology Axis, McMahon, Québec City, Canada.|Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Research Center, Québec City, Canada.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Caron
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Wouter W
authors.initials: WW
authors.lastname: Wiegant
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Diana
authors.initials: D
authors.lastname: van den Heuvel
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Rick A
authors.initials: RA
authors.lastname: Boonen
authors.affiliation: Genome Stability Laboratory, CHU de Québec Research Center, HDQ Pavilion, Oncology Axis, McMahon, Québec City, Canada.|Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Research Center, Québec City, Canada.
authors.forename: Anthony M
authors.identifier: 0000-0002-1512-9558
authors.initials: AM
authors.lastname: Couturier
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Leon H
authors.initials: LH
authors.lastname: Mullenders
authors.affiliation: Genome Stability Laboratory, CHU de Québec Research Center, HDQ Pavilion, Oncology Axis, McMahon, Québec City, Canada.|Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Research Center, Québec City, Canada.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Masson
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Haico
authors.identifier: 0000-0001-8590-0240
authors.initials: H
authors.lastname: van Attikum
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000528:radiation effects; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D000076164:Fanconi Anemia Complementation Group N Protein / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism* / Q000528:radiation effects; D057809:HEK293 Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D054018:Lasers, Excimer; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D059767:Recombinational DNA Repair; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D014965:X-Rays
chemical_list: D000076164:Fanconi Anemia Complementation Group N Protein; D006657:Histones; C512790:PALB2 protein, human; C492743:Rif1 protein, human; D034501:Telomere-Binding Proteins; D025801:Ubiquitin; D004247:DNA; C535210:RNF168 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: DNA repair; PALB2; RNF168; biochemistry; cell biology; chromatin; homologous recombination; human; ubiquitylation