title: Coupling of Homologous Recombination and the Checkpoint by ATR.
abstract: ATR is a key regulator of cell-cycle checkpoints and homologous recombination (HR). Paradoxically, ATR inhibits CDKs during checkpoint responses, but CDK activity is required for efficient HR. Here, we show that ATR promotes HR after CDK-driven DNA end resection. ATR stimulates the BRCA1-PALB2 interaction after DNA damage and promotes PALB2 localization to DNA damage sites. ATR enhances BRCA1-PALB2 binding at least in part by inhibiting CDKs. The optimal interaction of BRCA1 and PALB2 requires phosphorylation of PALB2 at S59, an ATR site, and hypo-phosphorylation of S64, a CDK site. The PALB2-S59A/S64E mutant is defective for localization to DNA damage sites and HR, whereas the PALB2-S59E/S64A mutant partially bypasses ATR for its localization. Thus, HR is a biphasic process requiring both high-CDK and low-CDK periods. As exemplified by the regulation of PALB2 by ATR, ATR promotes HR by orchestrating a "CDK-to-ATR switch" post-resection, directly coupling the checkpoint to HR.
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Rémi
authors.initials: R
authors.lastname: Buisson
authors.affiliation: CHU de Québec Research Center, Oncology Axis, Department of Molecular Biology, Medical Biochemistry, and Pathology, Laval University Cancer Research Center, Laval University, Québec City, QC G1V 0A6, Canada.
authors.forename: Joshi
authors.initials: J
authors.lastname: Niraj
authors.affiliation: CHU de Québec Research Center, Oncology Axis, Department of Molecular Biology, Medical Biochemistry, and Pathology, Laval University Cancer Research Center, Laval University, Québec City, QC G1V 0A6, Canada.
authors.forename: Amélie
authors.initials: A
authors.lastname: Rodrigue
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Chu Kwen
authors.initials: CK
authors.lastname: Ho
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Johannes
authors.initials: J
authors.lastname: Kreuzer
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
authors.forename: Tzeh Keong
authors.initials: TK
authors.lastname: Foo
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Emilie J-L
authors.initials: EJ
authors.lastname: Hardy
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada.
authors.forename: Graham
authors.initials: G
authors.lastname: Dellaire
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Haas
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Xia
authors.affiliation: CHU de Québec Research Center, Oncology Axis, Department of Molecular Biology, Medical Biochemistry, and Pathology, Laval University Cancer Research Center, Laval University, Québec City, QC G1V 0A6, Canada. Electronic address: jean-yves.masson@crchudequebec.ulaval.ca.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Masson
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: zou.lee@mgh.harvard.edu.
authors.forename: Lee
authors.initials: L
authors.lastname: Zou
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D000076164:Fanconi Anemia Complementation Group N Protein; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D059767:Recombinational DNA Repair; D015398:Signal Transduction; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D018844:Cyclin-Dependent Kinases
keywords: ATR; BRCA1; CDK; PALB2; checkpoint; homologous recombination