title: Cdk1 participates in BRCA1-dependent S phase checkpoint control in response to DNA damage.
abstract: Cdk2 and cdk1 are individually dispensable for cell-cycle progression in cancer cell lines because they are able to compensate for one another. However, shRNA-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated S phase cell-cycle arrest and the phosphorylation of a subset of ATR/ATM targets after DNA damage. Loss of DNA damage-induced checkpoint control was caused by a reduction in formation of BRCA1-containing foci. Mutation of BRCA1 at S1497 and S1189/S1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of BRCA1-containing foci. Abrogation of checkpoint control after cdk1 depletion or inhibition in non-small-cell lung cancer cells sensitized them to DNA-damaging agents. Conversely, reduced cdk1 activity caused more potent G2/M arrest in nontransformed cells and antagonized the response to subsequent DNA damage. Cdk1 inhibition may therefore selectively sensitize BRCA1-proficient cancer cells to DNA-damaging treatments by disrupting BRCA1 function.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Johnson
authors.forename: Dongpo
authors.initials: D
authors.lastname: Cai
authors.forename: Richard D
authors.initials: RD
authors.lastname: Kennedy
authors.forename: Shailja
authors.initials: S
authors.lastname: Pathania
authors.forename: Mansi
authors.initials: M
authors.lastname: Arora
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Li
authors.forename: Alan D
authors.initials: AD
authors.lastname: D'Andrea
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Parvin
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016203:CDC2 Protein Kinase / Q000378:metabolism / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016196:S Phase / Q000502:physiology*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase
references.citation: Mol Cell Biol. 1999 Jul;19(7):4843-54
references.pmid: 10373534
references.citation: Cancer Res. 2005 Feb 1;65(3):780-6
references.pmid: 15705874
references.citation: Nat Cell Biol. 2006 Jan;8(1):37-45
references.pmid: 16327781
references.citation: Mol Cell Biol. 2000 Nov;20(22):8602-12
references.pmid: 11046155
references.citation: Nature. 2004 Oct 21;431(7011):1011-7
references.pmid: 15496928
references.citation: J Biol Chem. 2008 Mar 21;283(12):7713-20
references.pmid: 18171670
references.citation: Int J Cancer. 2002 Dec 10;102(5):463-8
references.pmid: 12432547
references.citation: Nat Genet. 2002 Mar;30(3):285-9
references.pmid: 11836499
references.citation: Cancer Res. 2003 Oct 1;63(19):6221-8
references.pmid: 14559807
references.citation: EMBO J. 2003 Jun 2;22(11):2860-71
references.pmid: 12773400
references.citation: Cell. 1997 Aug 8;90(3):425-35
references.pmid: 9267023
references.citation: Cell. 1997 Jan 24;88(2):265-75
references.pmid: 9008167
references.citation: Nature. 2007 Nov 22;450(7169):509-14
references.pmid: 17965729
references.citation: Cancer Res. 2006 Aug 15;66(16):8219-26
references.pmid: 16912201
references.citation: Mol Cell. 2001 Feb;7(2):249-62
references.pmid: 11239454
references.citation: Cell Cycle. 2006 May;5(9):984-93
references.pmid: 16687918
references.citation: Cancer Res. 2006 Jan 1;66(1):435-44
references.pmid: 16397259
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 11;103(28):10660-5
references.pmid: 16818887
references.citation: Cancer Res. 2006 Jan 1;66(1):41-5
references.pmid: 16397213
references.citation: Cancer Cell. 2003 May;3(5):421-9
references.pmid: 12781359
references.citation: Mol Cell Biol. 2004 Oct;24(19):8457-66
references.pmid: 15367667
references.citation: Hum Mol Genet. 1995 Dec;4(12):2265-73
references.pmid: 8634697
references.citation: Cancer Res. 2006 Sep 15;66(18):9270-80
references.pmid: 16982772
references.citation: Genes Dev. 2001 Sep 1;15(17):2177-96
references.pmid: 11544175
references.citation: Nature. 2007 Aug 16;448(7155):811-5
references.pmid: 17700700