title: Haploinsufficiency of Parp1 accelerates Brca1-associated centrosome amplification, telomere shortening, genetic instability, apoptosis, and embryonic lethality.
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(+/Delta11)) with Parp1-null mice. We show that Brca1(Delta11/Delta11);Parp1(-/-) embryos die before embryonic (E) day 6.5, whereas Brca1(Delta11/Delta11) embryos die after E12.5, indicating that absence of Parp1 dramatically accelerates lethality caused by Brca1 deficiency. Surprisingly, haploinsufficiency of Parp1 in Brca1(Delta11/Delta11) embryos induces a severe chromosome aberrations, centrosome amplification, and telomere dysfunction, leading to apoptosis and accelerated embryonic lethality. Notably, telomere shortening in Brca1(Delta11/Delta11);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.
authors.affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.forename: C
authors.initials: C
authors.lastname: Montagna
authors.forename: T
authors.initials: T
authors.lastname: Ried
authors.forename: C-X
authors.initials: CX
authors.lastname: Deng
mesh_terms: D000483:Alleles; D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D017209:Apoptosis; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D018385:Centrosome / Q000378:metabolism*; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000378:metabolism; D020964:Embryo Loss / Q000235:genetics* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D042822:Genomic Instability; D005838:Genotype; D006238:Haploidy; D007621:Karyotyping; D000072200:Ku Autoantigen; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D009436:Neural Tube Defects / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency* / Q000235:genetics; D016615:Telomere / Q000235:genetics / Q000378:metabolism*
chemical_list: D034961:Antigens, Nuclear; D019313:BRCA1 Protein; D004268:DNA-Binding Proteins; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen