PARP1 Is a TRF2-associated Poly(ADP-Ribose)Polymerase and Protects Eroded Telomeres

Gomez, Marla; Wu, Jun; Schreiber, Valérie; Dunlap, John R.; Dantzer, Françoise; Wang, Yisong; Liu, Yie

doi:10.1091/mbc.e05-07-0672

Cited by 107 publications

(124 citation statements)

References 45 publications

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“…However, we cannot exclude that the different roles of PARP1 and PARP2 could be cell-and/or drug-type dependent. The activation of PARP1 upon G4-induced telomere damage is consistent with data showing that PARP1 localizes sporadically at undamaged telomeres, but preferentially at telomeres upon induction of DNA damage or loss of telomeric DNA (Gomez et al, 2006, and this paper). However, although nearly all the PAR spots induced by RHPS4 localized to telomeres, the poly-ADP ribosylation as well as PARP1 signals activated by other types of DNA-damaging agents are mostly detected at the non-telomeric regions (Gomez et al, 2006, and this paper).…”

Section: Discussionsupporting

confidence: 91%

“…Therefore, a reduced amount of TRF2 can prevent PARP recruitment and activation at telomeres, providing an explanation for the lack of poly-ADP ribosylation upon TRF2 dysfunction. It also has been reported that the poly-ADP ribosylation of telomeric proteins inhibits their telomeric DNA-binding activity (Gomez et al, 2006;Donigian and de Lange, 2007). Therefore, as we previously reported that RHPS4 leads to POT1 dissociation, we can speculate that, upon RHPS4 treatment, PARP1 catalyzes the poly-ADP ribosylation of POT1, leading to its dissociation from telomeres.…”

Section: Discussionsupporting

confidence: 52%

“…Tankyrases 1 and 2, as well as PARP1 and 2, can directly bind to and poly-ADP ribosylate the telomeric repeat binding factors 1 (TRF1) and 2 (TRF2) and affect their association to telomeric DNA, acting as positive regulators for telomere elongation (Smith and de Lange, 1999;Kaminker et al, 2001;Cook et al, 2002;Rippmann et al, 2002). In addition, upon DNA damage, PARP1 may be recruited to the damaged telomeres, helping to protect telomeres against chromosome end-to-end fusions and genomic instability (Gomez et al, 2006). PARP1, the founding member of the PARP family, and PARP2 have long been studied as DNA damage responsive enzymes required for maintaining genomic integrity (Ame´et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy

Salvati¹,

Scarsella²,

Porru³

et al. 2010

Oncogene

104

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New anti-telomere strategies represent important goals for the development of selective cancer therapies. In this study, we reported that uncapped telomeres, resulting from pharmacological stabilization of quadruplex DNA by RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino [4,3,2-kl]acridinium methosulfate), trigger specific recruitment and activation of poly-adenosine diphosphate (ADP) ribose polymerase I (PARP1) at the telomeres, forming several ADP-ribose polymers that co-localize with the telomeric repeat binding factor 1 protein and are inhibited by selective PARP(s) inhibitors or PARP1-specific small interfering RNAs. The knockdown of PARP1 prevents repairing of RHPS4-induced telomere DNA breaks, leading to increases in chromosome abnormalities and eventually to the inhibition of tumor cell growth both in vitro and in xenografts. More interestingly, the integration of a TOPO1 inhibitor on the combination treatment proved to have a high therapeutic efficacy ensuing a complete regression of the tumor as well as a significant increase in overall survival and cure of mice even when treatments started at a very late stage of tumor growth. Overall, this work reveals the unexplored link between the PARP1 and G-quadruplex ligands and demonstrates the excellent efficacy of a multicomponent strategy based on the use of PARP inhibitors in telomere-based therapy.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy

Salvati¹,

Scarsella²,

Porru³

et al. 2010

Oncogene

104

View full text Add to dashboard Cite

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“…Immunoprecipitation, Mass Spectrometric, and Data Analyses-Immunoprecipitation of endogenous B23, GCN5, and FLAG-tagged GCN5 was performed in essentially the same manner as described in our previous studies (29). For mass spectrometric analysis, asynchronized U2OS cells were treated with or without 0.2 g/ml nocodazole for 24 h and then lysed in a buffer containing 50 mM Tris-HCl, pH 8.0, 150 mM NaCl, 0.25% Nonidet P-40 and protease inhibitor mixture (Roche Applied Science).…”

Section: Methodsmentioning

confidence: 99%

Nucleophosmin/B23 Negatively Regulates GCN5-dependent Histone Acetylation and Transactivation

Zou

Giannone

et al. 2008

Journal of Biological Chemistry

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Nucleophosmin/B23 is a multifunctional phosphoprotein that is overexpressed in cancer cells and has been shown to be involved in both positive and negative regulation of transcription. In this study, we first identified GCN5 acetyltransferase as a B23-interacting protein by mass spectrometry, which was then confirmed by in vivo co-immunoprecipitation. An in vitro assay demonstrated that B23 bound the PCAF-N domain of GCN5 and inhibited GCN5-mediated acetylation of both free and mononucleosomal histones, probably through interfering with GCN5 and masking histones from being acetylated. Mitotic B23 exhibited higher inhibitory activity on GCN5-mediated histone acetylation than interphase B23. Immunodepletion experiments of mitotic extracts revealed that phosphorylation of B23 at Thr 199 enhanced the inhibition of GCN5-mediated histone acetylation. Moreover, luciferase reporter and microarray analyses suggested that B23 attenuated GCN5-mediated transactivation in vivo. Taken together, our studies suggest a molecular mechanism of B23 in the mitotic inhibition of GCN5-mediated histone acetylation and transactivation.The acetylation of nucleosomal histones by histone acetyltransferases (HATs) 5 has been known for several decades. Histone-modifying enzymes, such as GCN5 (general control of amino acid synthesis 5) in the Spt-Ada-Gcn5 acetyltransferase (SAGA) and Esa1p in the NuA4 complex, can acetylate specific lysine residues in histone N-terminal tails (1). According to the histone code hypothesis (2), site-specific acetylation of histone tails may trigger chromatin remodeling that leads to retention of effector proteins to active promoters and formation of transcriptionally active chromatin regions.GCN5 was originally identified as a transcriptional coactivator in yeast and was proposed to contribute to transcription by establishing interactions between certain activators and transcriptional complexes (3). GCN5 enhances transcription through its intrinsic acetyltransferase activity (4), which facilitates acetylation of histones and nonhistone substrates (3). Recruitment of the SAGA complex greatly increases transcriptional activation in vitro (5), and the requirement of GCN5 for chromatin remodeling has been demonstrated in vivo (6). However, the mechanism(s) that regulates GCN5 activity particularly in the context of histone acetylation has yet to be examined in detail. Potentially, GCN5 HAT activity can be regulated through posttranslational modifications, interacting with other proteins or at the level of substrate modifications. For example, phosphorylation by the Ku-DNA-dependent protein kinase or sumoylation may regulate GCN5-HAT activity (7,8). Also, interaction with the SANT domain of the Ada2 affects GCN5-HAT activity in yeast (9). Likewise, modification of substrates, such as phosphorylation of H3 serine 10, increases GCN5 acetylation activity toward lysine 14 of H3 (10, 11).Nucleophosmin/B23, also known as NPM1, NO38, or numatrin, has been identified as a phosphoprotein that possesses multiple cellular func...

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“…HeLa cells were lysed in buffer A (120 mM NaCl, 0.5% NP-40, 0.1 mM EDTA, 0.5 mM Tris-HCl, pH 8.0, 0.1 mM NaF, 0.1 mM Na 3 VO 4 , and 0.1 mM dithiothreitol) and incubated with or without 12.5 g/ml ethidium bromide for 30 min on ice (Gomez et al, 2006) or with 100 g/ml DNase I in the presence of 10 mM MgCl 2 for 30 min on ice (Ricke and Bielinsky, 2004). The lysate was centrifuged at 14,000 ϫ g in a precooled centrifuge for 10 min.…”

Section: Coimmunoprecipitationmentioning

confidence: 99%

Human Mcm10 Regulates the Catalytic Subunit of DNA Polymerase-α and Prevents DNA Damage during Replication

Chattopadhyay

Bielinsky

2007

MBoC

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In Saccharomyces cerevisiae, minichromosome maintenance protein (Mcm) 10 interacts with DNA polymerase (pol)-␣ and functions as a nuclear chaperone for the catalytic subunit, which is rapidly degraded in the absence of Mcm10. We report here that the interaction between Mcm10 and pol-␣ is conserved in human cells. We used a small interfering RNA-based approach to deplete Mcm10 in HeLa cells, and we observed that the catalytic subunit of pol-␣, p180, was degraded with similar kinetics as Mcm10, whereas the regulatory pol-␣ subunit, p68, remained unaffected. Simultaneous loss of Mcm10 and p180 inhibited S phase entry and led to an accumulation of already replicating cells in late S/G2 as a result of DNA damage, which triggered apoptosis in a subpopulation of cells. These phenotypes differed considerably from analogous studies in Drosophila embryo cells that did not exhibit a similar arrest. To further dissect the roles of Mcm10 and p180 in human cells, we depleted p180 alone and observed a significant delay in S phase entry and fork progression but little effect on cell viability. These results argue that cells can tolerate low levels of p180 as long as Mcm10 is present to "recycle" it. Thus, human Mcm10 regulates both replication initiation and elongation and maintains genome integrity. INTRODUCTIONDNA replication is a highly regulated process in which multiprotein complexes generate an exact copy of a cell's DNA. These multiprotein complexes are assembled into replication forks. Fork assembly takes place at replication origins that are spread throughout the genome in all eukaryotic cells. The first step is the formation of a prereplicative complex (pre-RC) (Diffley et al., 1994), which is subsequently transformed into a preinitiation complex, and finally into a pair of functional replication forks that have the ability to unwind parental DNA and synthesize new daughter strands (Mendez and Stillman, 2003). DNA unwinding is likely catalyzed by the minichromosome maintenance (Mcm) 2-7 complex (Aparicio et al., 1997;Labib et al., 2000;Shechter et al., 2004) in conjunction with two coactivators, Cdc45 and GINS (Pacek and Walter, 2004;Gambus et al., 2006;Moyer et al., 2006;Pacek et al., 2006). The association of Cdc45 and GINS with DNA is interdependent (Kubota et al., 2003;Takayama et al., 2003), and it requires yet another factor, Mcm10 (Wohlschlegel et al., 2002;Gregan et al., 2003;Sawyer et al., 2004). Despite its name, Mcm10 is not a member of the MCM protein family, although it was isolated in the same genetic screen in budding yeast that identified the MCM2-7 genes (Solomon et al., 1992;Merchant et al., 1997).Mcm10 is a constitutively nuclear DNA binding protein (Merchant et al., 1997;Burich and Lei, 2003) that is essential in yeast (Burich and Lei, 2003). Besides its role in DNA replication, Mcm10 has also been implicated in transcriptional silencing (Liachko and Tye, 2005). It is important to note that the general protein domain structure of Mcm10 is not unique in Saccharomyces cerevisiae, but it is highly con...

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PARP1 Is a TRF2-associated Poly(ADP-Ribose)Polymerase and Protects Eroded Telomeres

Cited by 107 publications

References 45 publications

PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy

PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy

Nucleophosmin/B23 Negatively Regulates GCN5-dependent Histone Acetylation and Transactivation

Human Mcm10 Regulates the Catalytic Subunit of DNA Polymerase-α and Prevents DNA Damage during Replication

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