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

Wang, X; Liu, Lei; Montagna, Cristina; Ried, Thomas; Cx, Deng

doi:10.1038/sj.cdd.4402105

Cited by 25 publications

(19 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with this idea, overexpression of BRCA1 by itself increased overhang length but did not effectively rescue the reduction in overhang length due to Rad50 knockdown, and combined knockdown of Rad50 and BRCA1 did not reduce overhang length below that due to Rad50 siRNA alone. Our findings are consistent with previous reports that cells with no functional BRCA1 show chromosomal anomalies suggestive of telomere dysfunction (33)(34)(35). It was also reported that disruption of BRCA1 function (via a dominant negative mutant BRCA1) caused appearance of anaphase bridges and increased telomere length in a telomerase-positive cell line (36).…”

Section: Discussionsupporting

confidence: 83%

BRCA1 Localization to the Telomere and Its Loss from the Telomere in Response to DNA Damage

Ballal¹,

Saha

Fan

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

BRCA1, a tumor suppressor, participates in DNA damage signaling and repair. Previously, we showed that BRCA1 overexpression caused inhibition of telomerase activity and telomere shortening in breast and prostate cancer cells. We now report that BRCA1 knockdown causes increased telomerase reverse transcriptase expression, telomerase activity, and telomere length; but studies utilizing a combination of BRCA1 and telomerase reverse transcriptase small interfering RNAs suggest that BRCA1 also regulates telomere length independently of telomerase. Using telomeric chromatin immunoprecipitation assays, we detected BRCA1 at the telomere and demonstrated time-dependent loss of BRCA1 from the telomere following DNA damage. Further studies suggest that BRCA1 interacts with TRF1 and TRF2 in a DNA-dependent manner and that some of the nuclear BRCA1 colocalizes with TRF1/2. Our findings further suggest that Rad50 is required to localize BRCA1 at the telomere and that the association of BRCA1 with Rad50 does not require DNA. Finally, we found that BRCA1 regulates the length of the 3 G-rich overhang in a manner that is dependent upon Rad50. Our findingssuggestthatBRCA1isrecruitedtothetelomereinaRad50-dependent manner and that BRCA1 may regulate telomere length and stability, in part through its presence at the telomere.

show abstract

Section: Discussionsupporting

confidence: 83%

BRCA1 Localization to the Telomere and Its Loss from the Telomere in Response to DNA Damage

Ballal¹,

Saha

Fan

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Short telomeres also can reduce homologous pairing and recombination, and cause meiotic abnormality including aberrant chromosome alignment at metaphase and disruption of spindles, resulting in aneuploidy [41][42][43]. Notably, BRCA1/2 is involved in telomere maintenance [44][45][46][47][48]. Interestingly, telomere shortening also alters kinetics of the DNA double strand break repair in response to ionization radiation in human cells [49].…”

Section: Potential Role Of Dna Dsb Repair and Brca Genes In Oocyte Qumentioning

confidence: 94%

BRCA Mutations, DNA Repair Deficiency, and Ovarian Aging1

Oktay

Turan

Titus

et al. 2015

Biology of Reproduction

138

View full text Add to dashboard Cite

Oocyte aging has a significant impact on reproductive outcomes both quantitatively and qualitatively. However, the molecular mechanisms underlying the age-related decline in reproductive success have not been fully addressed. BRCA is known to be involved in homologous DNA recombination and plays an essential role in double-strand DNA break repair. Given the growing body of laboratory and clinical evidence, we performed a systematic review on the current understanding of the role of DNA repair in human reproduction. We find that BRCA mutations negatively affect ovarian reserve based on convincing evidence from in vitro and in vivo results and prospective studies. Because decline in the function of the intact gene occurs at an earlier age, women with BRCA1 mutations exhibit accelerated ovarian aging, unlike those with BRCA2 mutations. However, because of the still robust function of the intact allele in younger women and because of the masking of most severe cases by prophylactic oophorectomy or cancer, it is less likely one would see an effect of BRCA mutations on fertility until later in reproductive age. The impact of BRCA2 mutations on reproductive function may be less visible because of the delayed decline in the function of normal BRCA2 allele. BRCA1 function and ataxia-telangiectasia-mutated (ATM)-mediated DNA repair may also be important in the pathogenesis of age-induced increase in aneuploidy. BRCA1 is required for meiotic spindle assembly, and cohesion function between sister chromatids is also regulated by ATM family member proteins. Taken together, these findings strongly suggest the implication of BRCA and DNA repair malfunction in ovarian aging.

show abstract

“…As ATM generates ␥-H2AX at DSBs (11), this finding may suggest a common mechanism for embryonic lethality in PARP1/ATM and PARP1/H2AX mice. In this regard, both ATM and H2AX function to facilitate repair via HR, pointing to synthetic lethality due to combined impairment of BER and HR as a potential mechanism operating in both models (8,10,21,42,66). In this context, ATM-dependent formation of ␥-H2AX promotes HR via the establishment of a platform that facilitates cohesin-mediated assembly of sister chromatids prior to recombination (64), kinase cross talk (13), and possibly other mechanisms (71).…”

Section: Discussionmentioning

confidence: 99%

Differential Requirement for H2AX and 53BP1 in Organismal Development and Genome Maintenance in the Absence of Poly(ADP)ribosyl Polymerase 1

Orsburn

Escudero

Prakash

et al. 2010

Molecular and Cellular Biology

View full text Add to dashboard Cite

Combined deficiencies of poly(ADP)ribosyl polymerase 1 (PARP1) and ataxia telangiectasia mutated (ATM) result in synthetic lethality and, in the mouse, early embryonic death. Here, we investigated the genetic requirements for this lethality via analysis of mice deficient for PARP1 and either of two ATM-regulated DNA damage response (DDR) factors: histone H2AX and 53BP1. We found that, like ATM, H2AX is essential for viability in a PARP1-deficient background. In contrast, deficiency for 53BP1 modestly exacerbates phenotypes of growth retardation, genomic instability, and organismal radiosensitivity observed in PARP1-deficient mice. To gain mechanistic insights into these different phenotypes, we examined roles for 53BP1 in the repair of replication-associated double-strand breaks (DSBs) in several cellular contexts. We show that 53BP1 is required for DNA-PKcs-dependent repair of hydroxyurea (HU)-induced DSBs but dispensable for RPA/ RAD51-dependent DSB repair in the same setting. Moreover, repair of mitomycin C (MMC)-induced DSBs and sister chromatid exchanges (SCEs), two RAD51-dependent processes, are 53BP1 independent. Overall, our findings define 53BP1 as a main facilitator of nonhomologous end joining (NHEJ) during the S phase of the cell cycle, beyond highly specialized lymphocyte rearrangements. These findings have important implications for our understanding of the mechanisms whereby ATM-regulated DDR prevents human aging and cancer.DNA double-strand breaks (DSBs) arise constantly in mammalian cells from endogenous and exogenous sources (35). Defective DSB repair leading to cellular senescence or apoptosis, or aberrant repair to form chromosomal rearrangements, has been linked to aging and cancer in humans (22, 31). To prevent these deleterious outcomes, mammalian cells have evolved the DNA damage response (DDR), a network of factors that sense and signal DSBs to promote their repair (29). ataxia telangiectasia mutated (ATM) is a phophoinositide 3-kinase (PI3K)-like kinase that regulates the functions of hundreds of substrates during DDR, including histone H2AX and 53BP1 (41). Ultimately, the DDR restores DNA strand continuity via either of two main DSB repair pathways: homologous recombination (HR), an error-free pathway that operates only during the S/G 2 phases (70), or nonhomologous end joining (NHEJ), a versatile but error-prone pathway that operates throughout the cell cycle (37, 44).Poly(ADP)ribosyl polymerase 1 (PARP1) regulates, among other processes, transcription, cell death, and DNA repair (57). In the last context, PARP1 senses single-strand breaks (SSBs) and promotes their repair via base excision repair (BER) (15). Although PARP1 is not a component of the BER pathway per se, PARP1-deficient cells accumulate SSBs, which become substrates for HR-mediated repair upon replication (10, 21). ATM and other DDR factors may play important roles in DSB recognition and recruitment of the HR machinery in this setting (42). In addition, PARP1 also catalyzes PAR formation at de novo-generated DNA DSBs (28...

show abstract

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

Cited by 25 publications

References 39 publications

BRCA1 Localization to the Telomere and Its Loss from the Telomere in Response to DNA Damage

BRCA1 Localization to the Telomere and Its Loss from the Telomere in Response to DNA Damage

BRCA Mutations, DNA Repair Deficiency, and Ovarian Aging1

Differential Requirement for H2AX and 53BP1 in Organismal Development and Genome Maintenance in the Absence of Poly(ADP)ribosyl Polymerase 1

Contact Info

Product

Resources

About