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

共 44 条

[1] 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers [J].

Bouwman, Peter ;

Aly, Amal ;

Escandell, Jose M. ;

Pieterse, Mark ;

Bartkova, Jirina ;

van der Gulden, Hanneke ;

Hiddingh, Sanne ;

Thanasoula, Maria ;

Kulkarni, Atul ;

Yang, Qifeng ;

Haffty, Bruce G. ;

Tommiska, Johanna ;

Blomqvist, Carl ;

Drapkin, Ronny ;

Adams, David J. ;

Nevanlinna, Heli ;

Bartek, Jiri ;

Tarsounas, Madalena ;

Ganesan, Shridar ;

Jonkers, Jos .

NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2010, 17 (06) :688-U56

[2] Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase [J].

Bryant, HE ;

Schultz, N ;

Thomas, HD ;

Parker, KM ;

Flower, D ;

Lopez, E ;

Kyle, S ;

Meuth, M ;

Curtin, NJ ;

Helleday, T .

NATURE, 2005, 434 (7035) :913-917

[3] PARP is activated at stalled forks to mediate Mre11-dependent replication restart and recombination [J].

Bryant, Helen E. ;

Petermann, Eva ;

Schultz, Niklas ;

Jemth, Ann-Sofie ;

Loseva, Olga ;

Issaeva, Natalia ;

Johansson, Fredrik ;

Fernandez, Serena ;

McGlynn, Peter ;

Helleday, Thomas .

EMBO JOURNAL, 2009, 28 (17) :2601-2615

[4] 53BP1 Inhibits Homologous Recombination in Brca1-Deficient Cells by Blocking Resection of DNA Breaks [J].

Bunting, Samuel F. ;

Callen, Elsa ;

Wong, Nancy ;

Chen, Hua-Tang ;

Polato, Federica ;

Gunn, Amanda ;

Bothmer, Anne ;

Feldhahn, Niklas ;

Fernandez-Capetillo, Oscar ;

Cao, Liu ;

Xu, Xiaoling ;

Deng, Chu-Xia ;

Finkel, Toren ;

Nussenzweig, Michel ;

Stark, Jeremy M. ;

Nussenzweig, Andre .

CELL, 2010, 141 (02) :243-254

[5] ATM prevents the persistence and propagation of chromosome breaks in lymphocytes [J].

Callen, Elsa ;

Jankovic, Mila ;

Difilippantonio, Simone ;

Daniel, Jeremy A. ;

Chen, Hua-Tang ;

Celeste, Arkady ;

Pellegrini, Manuela ;

McBride, Kevin ;

Wangsa, Danny ;

Bredemeyer, Andrea L. ;

Sleckman, Barry P. ;

Ried, Thomas ;

Nussenzweig, Michel ;

Nussenzweig, Andre .

CELL, 2007, 130 (01) :63-75

[6] Replication fork stability confers chemoresistance in BRCA-deficient cells [J].

Chaudhuri, Arnab Ray ;

Callen, Elsa ;

Ding, Xia ;

Gogola, Ewa ;

Duarte, Alexandra A. ;

Lee, Ji-Eun ;

Wong, Nancy ;

Lafarga, Vanessa ;

Calvo, Jennifer A. ;

Panzarino, Nicholas J. ;

John, Sam ;

Day, Amanda ;

Crespo, Anna Vidal ;

Shen, Binghui ;

Starnes, Linda M. ;

de Ruiter, Julian R. ;

Daniel, Jeremy A. ;

Konstantinopoulos, Panagiotis A. ;

Cortez, David ;

Cantor, Sharon B. ;

Fernandez-Capetillo, Oscar ;

Ge, Kai ;

Jonkers, Jos ;

Rottenberg, Sven ;

Sharan, Shyam K. ;

Nussenzweig, Andre .

NATURE, 2016, 535 (7612) :382-+

[7] Topoisomerase I poisoning results in PARP-mediated replication fork reversal [J].

Chaudhuri, Arnab Ray ;

Hashimoto, Yoshitami ;

Herrador, Raquel ;

Neelsen, Kai J. ;

Fachinetti, Daniele ;

Bermejo, Rodrigo ;

Cocito, Andrea ;

Costanzo, Vincenzo ;

Lopes, Massimo .

NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2012, 19 (04) :417-423

[8] Involvement of poly(ADP-ribose) polymerase in base excision repair [J].

Dantzer, F ;

Schreiber, V ;

Niedergang, C ;

Trucco, C ;

Flatter, E ;

De la Rubia, G ;

Oliver, J ;

Rolli, V ;

Ménissier-de Murcia, J ;

de Murcia, G .

BIOCHIMIE, 1999, 81 (1-2) :69-75

[9] Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy [J].

Farmer, H ;

McCabe, N ;

Lord, CJ ;

Tutt, ANJ ;

Johnson, DA ;

Richardson, TB ;

Santarosa, M ;

Dillon, KJ ;

Hickson, I ;

Knights, C ;

Martin, NMB ;

Jackson, SP ;

Smith, GCM ;

Ashworth, A .

NATURE, 2005, 434 (7035) :917-921

[10] Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers. [J].

Fong, Peter C. ;

Boss, David S. ;

Yap, Timothy A. ;

Tutt, Andrew ;

Wu, Peijun ;

Mergui-Roelvink, Marja ;

Mortimer, Peter ;

Swaisland, Helen ;

Lau, Alan ;

O'Connor, Mark J. ;

Ashworth, Alan ;

Carmichael, James ;

Kaye, Stan B. ;

Schellens, Jan H. M. ;

de Bono, Johann S. .

NEW ENGLAND JOURNAL OF MEDICINE, 2009, 361 (02) :123-134

← 1 2 3 4 5 →