Haploinsufficiency of Parp1 accelerates Brca1-associated centrosome amplification, telomere shortening, genetic instability, apoptosis, and embryonic lethality

X. Wang, L. Liu, C. Montagna, T. Ried, C. X. Deng

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

The breast tumor associated gene-1 (BRCA1) and poly(ADP-ribose) polymerase-1 (PARP1) are both involved in DNA-damage response and DNA-damage repair. Recent investigations have suggested that inhibition of PARP1 represents a promising chemopreventive/therapeutic approach for specifically treating BRCA1- and BRCA2-associated breast cancer. However, studies in mouse models reveal that Parp1-null mutation results in genetic instability and mammary tumor formation, casting significant doubt on the safety of PARP1 inhibition as a therapy for the breast cancer. To study the genetic interactions between Brca1 and Parp1, we interbred mice carrying a heterozygous deletion of full-length Brca1 (Brca1+/Δ11) with Parp1-null mice. We show that Brca1Δ11/Δ11;Parp1-/- embryos die before embryonic (E) day 6.5, whereas Brca1Δ11/Δ11 embryos die after E12.5, indicating that absence of Parp1 dramatically accelerates lethality caused by Brca1 deficiency. Surprisingly, haploinsufficiency of Parp1 in Brca1Δ11/Δ11 embryos induces a severe chromosome aberrations, centrosome amplification, and telomere dysfunction, leading to apoptosis and accelerated embryonic lethality. Notably, telomere shortening in Brca1Δ11/Δ11;Parp1+/- MEFs was correlated with decreased expression of Ku70, which plays an important role in telomere maintenance. Thus, haploid loss of Parp1 is sufficient to induce lethality of Brca1-deficient cells, suggesting that partial inhibition of PARP1 may represent a practical chemopreventive/therapeutic approach for BRCA1-associated breast cancer.

Original languageEnglish (US)
Pages (from-to)924-931
Number of pages8
JournalCell Death and Differentiation
Volume14
Issue number5
DOIs
StatePublished - May 1 2007
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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