Synthetic viability by BRCA2 and PARP1/ARTD1 deficiencies

Xia Ding; Arnab Ray Chaudhuri; Elsa Callen; Yan Pang; Kajal Biswas; Kimberly D. Klarmann; Betty K. Martin; Sandra Burkett; Linda Cleveland; Stacey Stauffer; Teresa Sullivan; Aashish Dewan; Hanna Marks; Anthony T. Tubbs; Nancy Wong; Eugen Buehler; Keiko Akagi; Scott E. Martin; Jonathan R. Keller; André Nussenzweig; Shyam K. Sharan

doi:10.1038/ncomms12425

Synthetic viability by BRCA2 and PARP1/ARTD1 deficiencies

Xia Ding, Arnab Ray Chaudhuri, Elsa Callen, Yan Pang, Kajal Biswas, Kimberly D. Klarmann, Betty K. Martin, Sandra Burkett, Linda Cleveland, Stacey Stauffer, Teresa Sullivan, Aashish Dewan, Hanna Marks, Anthony T. Tubbs, Nancy Wong, Eugen Buehler, Keiko Akagi, Scott E. Martin, Jonathan R. Keller, André NussenzweigShyam K. Sharan

Research output: Contribution to journal › Article › peer-review

102 Scopus citations

Abstract

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 Brca2 ko/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.

Original language	English (US)
Article number	12425
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms12425
State	Published - Aug 8 2016
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/ncomms12425

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Ding, X., Chaudhuri, A. R., Callen, E., Pang, Y., Biswas, K., Klarmann, K. D., Martin, B. K., Burkett, S., Cleveland, L., Stauffer, S., Sullivan, T., Dewan, A., Marks, H., Tubbs, A. T., Wong, N., Buehler, E., Akagi, K., Martin, S. E., Keller, J. R., ... Sharan, S. K. (2016). Synthetic viability by BRCA2 and PARP1/ARTD1 deficiencies. Nature communications, 7, Article 12425. https://doi.org/10.1038/ncomms12425

Ding, X, Chaudhuri, AR, Callen, E, Pang, Y, Biswas, K, Klarmann, KD, Martin, BK, Burkett, S, Cleveland, L, Stauffer, S, Sullivan, T, Dewan, A, Marks, H, Tubbs, AT, Wong, N, Buehler, E, Akagi, K, Martin, SE, Keller, JR, Nussenzweig, A & Sharan, SK 2016, 'Synthetic viability by BRCA2 and PARP1/ARTD1 deficiencies', Nature communications, vol. 7, 12425. https://doi.org/10.1038/ncomms12425

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title = "Synthetic viability by BRCA2 and PARP1/ARTD1 deficiencies",

abstract = "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 Brca2 ko/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.",

author = "Xia Ding and Chaudhuri, {Arnab Ray} and Elsa Callen and Yan Pang and Kajal Biswas and Klarmann, {Kimberly D.} and Martin, {Betty K.} and Sandra Burkett and Linda Cleveland and Stacey Stauffer and Teresa Sullivan and Aashish Dewan and Hanna Marks and Tubbs, {Anthony T.} and Nancy Wong and Eugen Buehler and Keiko Akagi and Martin, {Scott E.} and Keller, {Jonathan R.} and Andr{\'e} Nussenzweig and Sharan, {Shyam K.}",

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doi = "10.1038/ncomms12425",

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AU - Ding, Xia

AU - Chaudhuri, Arnab Ray

AU - Callen, Elsa

AU - Pang, Yan

AU - Biswas, Kajal

AU - Klarmann, Kimberly D.

AU - Martin, Betty K.

AU - Burkett, Sandra

AU - Cleveland, Linda

AU - Stauffer, Stacey

AU - Sullivan, Teresa

AU - Dewan, Aashish

AU - Marks, Hanna

AU - Tubbs, Anthony T.

AU - Wong, Nancy

AU - Buehler, Eugen

AU - Akagi, Keiko

AU - Martin, Scott E.

AU - Keller, Jonathan R.

AU - Nussenzweig, André

AU - Sharan, Shyam K.

PY - 2016/8/8

Y1 - 2016/8/8

N2 - 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 Brca2 ko/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.

AB - 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 Brca2 ko/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.

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Synthetic viability by BRCA2 and PARP1/ARTD1 deficiencies

Abstract

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