title: PARP1 Links CHD2-Mediated Chromatin Expansion and H3.3 Deposition to DNA Repair by Non-homologous End-Joining.
abstract: The response to DNA double-strand breaks (DSBs) requires alterations in chromatin structure to promote the assembly of repair complexes on broken chromosomes. Non-homologous end-joining (NHEJ) is the dominant DSB repair pathway in human cells, but our understanding of how it operates in chromatin is limited. Here, we define a mechanism that plays a crucial role in regulating NHEJ in chromatin. This mechanism is initiated by DNA damage-associated poly(ADP-ribose) polymerase 1 (PARP1), which recruits the chromatin remodeler CHD2 through a poly(ADP-ribose)-binding domain. CHD2 in turn triggers rapid chromatin expansion and the deposition of histone variant H3.3 at sites of DNA damage. Importantly, we find that PARP1, CHD2, and H3.3 regulate the assembly of NHEJ complexes at broken chromosomes to promote efficient DNA repair. Together, these findings reveal a PARP1-dependent process that couples ATP-dependent chromatin remodeling with histone variant deposition at DSBs to facilitate NHEJ and safeguard genomic stability.
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, the Netherlands. Electronic address: m.luijsterburg@lumc.nl.
authors.forename: Martijn S
authors.initials: MS
authors.lastname: Luijsterburg
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Inge
authors.initials: I
authors.lastname: de Krijger
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, the Netherlands.
authors.forename: Wouter W
authors.initials: WW
authors.lastname: Wiegant
authors.affiliation: Laboratory for Skin Cancer Research, CHU-Q: University Hospital Research Centre of Quebec (CHUL site) and Laval University, Quebec City, QC G1V 4G2, Canada.
authors.forename: Rashmi G
authors.initials: RG
authors.lastname: Shah
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, the Netherlands.
authors.forename: Godelieve
authors.initials: G
authors.lastname: Smeenk
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, the Netherlands.
authors.forename: Anton J L
authors.initials: AJL
authors.lastname: de Groot
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, the Netherlands.
authors.forename: Alex
authors.initials: A
authors.lastname: Pines
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, the Netherlands.
authors.forename: Alfred C O
authors.initials: ACO
authors.lastname: Vertegaal
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Jacqueline J L
authors.initials: JJL
authors.lastname: Jacobs
authors.affiliation: Laboratory for Skin Cancer Research, CHU-Q: University Hospital Research Centre of Quebec (CHUL site) and Laval University, Quebec City, QC G1V 4G2, Canada.
authors.forename: Girish M
authors.initials: GM
authors.lastname: Shah
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, the Netherlands. Electronic address: h.van.attikum@lumc.nl.
authors.forename: Haico
authors.initials: H
authors.lastname: van Attikum
mesh_terms: D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics*; D042002:Chromatin Assembly and Disassembly; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D004268:DNA-Binding Proteins / Q000378:metabolism*; D042822:Genomic Instability; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*
chemical_list: C575189:CHD2 protein, human; D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases