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.
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Abbreviations
- BRCA1:
-
Breast cancer associated gene 1
- PARP1:
-
Poly(ADP-ribose) polymerase 1
- SKY:
-
spectral karyotyping analysis
- Q-FISH:
-
quantitative fluorescence in situ hybridization
- DSBs:
-
DNA double-strand breaks
- SSB:
-
Single-strand breaks
- HR:
-
Homologous recombination
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Acknowledgements
We thank members of Deng laboratory for critical reading and discussion of the manuscript. We thank Dr. ZQ Wang for providing Parp1-deficient mice. This work was supported by the intramural Research Program of National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, USA.
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Wang, X., Liu, L., Montagna, C. et al. Haploinsufficiency of Parp1 accelerates Brca1-associated centrosome amplification, telomere shortening, genetic instability, apoptosis, and embryonic lethality. Cell Death Differ 14, 924–931 (2007). https://doi.org/10.1038/sj.cdd.4402105
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DOI: https://doi.org/10.1038/sj.cdd.4402105
