Involvement of Poly(ADP-Ribose) Polymerase 1 and Poly(ADP-Ribosyl)ation in Regulation of Centrosome Function

Kanai, Masayuki; Tong, Wei‐Min; Sugihara, Eiji; Wang, Zhaoqi; Fukasawa, Kenji; Misawa, Miwa

doi:10.1128/mcb.23.7.2451-2462.2003

Cited by 136 publications

(117 citation statements)

References 64 publications

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“…Our data also revealed centrosome amplification in about 25% of Parp1 À/À MEFs. This observation is consistent with a previous finding that absence of Parp1 causes centrosome hyperamplification, 25 and it provides a basis for the elevated centrosome number in the Brca1 D11/D11 ;Parp1 þ /À MEF.…”

Section: D11/d11supporting

confidence: 82%

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

et al. 2007

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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 þ /D11 ) with Parp1-null mice. We show that Brca1 D11/D11 ;Parp1 À/À embryos die before embryonic (E) day 6.5, whereas Brca1 D11/D11 embryos die after E12.5, indicating that absence of Parp1 dramatically accelerates lethality caused by Brca1 deficiency. Surprisingly, haploinsufficiency of Parp1 in Brca1 D11/D11 embryos induces a severe chromosome aberrations, centrosome amplification, and telomere dysfunction, leading to apoptosis and accelerated embryonic lethality. Notably, telomere shortening in Brca1 D11/D11 ;Parp1 þ /À 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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Section: D11/d11supporting

confidence: 82%

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

et al. 2007

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“…At least two other centrosomal proteins Cep76 [22] and Cep170 [23] contain RXXPDG TNKS1 binding sites and a number of other centrosomal proteins contain degenerate motifs, raising the possibility that TNKS could regulate stability of additional centrosomal proteins. Previous studies have demonstrated localization of other PARPs (PARP1 [24] and PARP3 [25]) to interphase centrosomes and PARP1 was found to be required for maintenance of proper centrosome number [26]. Hence, PARsylation (through multiple PARPs and targets) may have a general role in centrosome function.…”

Section: Resultsmentioning

confidence: 98%

Tankyrase 1 regulates centrosome function by controlling CPAP stability

2012

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CPAP-a gene mutated in primary microcephaly-is required for procentriole formation. Here we show that CPAP degradation and function is controlled by the poly(ADP-ribose) polymerase tankyrase 1. CPAP is PARsylated by tankyrase 1 in vitro and in vivo. Overexpression of tankyrase 1 leads to CPAP proteasomal degradation, preventing centriole duplication, whereas depletion of tankyrase 1 stabilizes CPAP in G1, generating elongated procentrioles and multipolarity. Tankyrase 1 localizes to centrosomes exclusively in G1, coinciding with CPAP degradation. Hence, tankyrase 1-mediated PARsylation regulates CPAP levels during the cell cycle to limit centriole elongation and ensure normal centrosome function.

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“…The failure to remove PAR from either covalently modified proteins or noncovalently bound PAR may lead to growth arrest and cell death, because many PAR-modified proteins are important for cell survival and DNA processing͞repair (37)(38)(39)(40)(41). Recent evidence suggests that poly-(ADP-ribosyl)ation regulates transcription (5) and that the failure to degrade PAR polymer may lead to transcriptional dysregulation.…”

Section: Discussionmentioning

confidence: 99%

Failure to degrade poly(ADP-ribose) causes increased sensitivity to cytotoxicity and early embryonic lethality

Koh

Lawler

Poitras

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

290

288

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The metabolism of poly(ADP-ribose) (PAR) is critical for genomic stability in multicellular eukaryotes. Here, we show that the failure to degrade PAR by means of disruption of the murine poly(ADPribose) glycohydrolase (PARG) gene unexpectedly causes early embryonic lethality and enhanced sensitivity to genotoxic stress. This lethality results from the failure to hydrolyze PAR, because PARG null embryonic day (E) 3.5 blastocysts accumulate PAR and concurrently undergo apoptosis. Moreover, embryonic trophoblast stem cell lines established from early PARG null embryos are viable only when cultured in medium containing the poly(ADPribose) polymerase inhibitor benzamide. Cells lacking PARG also show reduced growth, accumulation of PAR, and increased sensitivity to cytotoxicity induced by N-methyl-N -nitro-N-nitrosoguanidine and menadione after benzamide withdrawal. These results provide compelling evidence that the failure to degrade PAR has deleterious consequences. Further, they define a role for PARG in embryonic development and a protective role in the response to genotoxic stress.poly(ADP-ribose) glycohydrolase ͉ poly(ADP-ribose) polymerase ͉ apoptosis

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Involvement of Poly(ADP-Ribose) Polymerase 1 and Poly(ADP-Ribosyl)ation in Regulation of Centrosome Function

Cited by 136 publications

References 64 publications

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

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

Tankyrase 1 regulates centrosome function by controlling CPAP stability

Failure to degrade poly(ADP-ribose) causes increased sensitivity to cytotoxicity and early embryonic lethality

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