Synthetic viability by BRCA2 and PARP1/ARTD1 deficiencies

被引：100

作者：

Ding, Xia ^{[1
]}

Chaudhuri, Arnab Ray ^{[2
]}

Callen, Elsa ^{[2
]}

Pang, Yan ^{[1
]}

Biswas, Kajal ^{[1
]}

Klarmann, Kimberly D. ^{[1
,3
]}

Martin, Betty K. ^{[1
,3
]}

Burkett, Sandra ^{[1
]}

Cleveland, Linda ^{[1
]}

Stauffer, Stacey ^{[1
]}

Sullivan, Teresa ^{[1
]}

Dewan, Aashish ^{[1
]}

Marks, Hanna ^{[1
]}

Tubbs, Anthony T. ^{[2
]}

Wong, Nancy ^{[2
]}

Buehler, Eugen ^{[4
]}

Akagi, Keiko ^{[5
]}

Martin, Scott E. ^{[4
,6
]}

Keller, Jonathan R. ^{[1
,3
]}

Nussenzweig, Andre ^{[2
]}

Sharan, Shyam K. ^{[1
]}

机构：

[1] NCI, Mouse Canc Genet Program, NIH, Frederick, MD 21702 USA

[2] NCI, Lab Genome Integr, NIH, Bethesda, MD 20893 USA

[3] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA

[4] NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA

[5] Ohio State Univ, Ctr Comprehens Canc, Human Canc Genet Program, Columbus, OH 43210 USA

[6] Genentech Inc, Dept Discovery Oncol, San Francisco, CA 94080 USA

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

基金：

美国国家卫生研究院;

关键词：

OLAPARIB MAINTENANCE THERAPY; POLY(ADP-RIBOSE) POLYMERASE; HOMOLOGOUS RECOMBINATION; REPLICATION FORKS; MUTANT-CELLS; DNA-REPAIR; PARP; LETHALITY; DEGRADATION; INHIBITION;

D O I：

10.1038/ncomms12425

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) olaparib has been approved for treatment of advanced ovarian cancer associated with BRCA1 and BRCA2 mutations. BRCA1-and BRCA2-mutated cells, which are homologous recombination (HR) deficient, are hypersensitive to PARPi through the mechanism of synthetic lethality. Here we examine the effect of PARPi on HR-proficient cells. Olaparib pretreatment, PARP1 knockdown or Parp1 heterozygosity of Brca2(cko/ko) mouse embryonic stem cells (mESCs), carrying a null (ko) and a conditional (cko) allele of Brca2, results in viable Brca2ko/ko cells. PARP1 deficiency does not restore HR in Brca2(ko/ko) cells, but protects stalled replication forks from MRE11-mediated degradation through its impaired recruitment. The functional consequence of Parp1 heterozygosity on BRCA2 loss is demonstrated by a significant increase in tumorigenesis in Brca2(cko/cko) mice. Thus, while olaparib efficiently kills BRCA2-deficient cells, we demonstrate that it can also contribute to the synthetic viability if PARP is inhibited before BRCA2 loss.

引用

页数：12

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