P21Cip1/WAF1 downregulation is required for efficient PCNA ubiquitination after UV irradiation

Soria, Gastón; Podhajcer, Osvaldo L.; Prives, Carol; Gottifredi, Vanesa

doi:10.1038/sj.onc.1209315

Cited by 98 publications

(131 citation statements)

References 53 publications

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“…PCNA is also monoubiquitinated in response to a variety of other DNA damaging agents, including methyl methanesulfonate (MMS), mitomycine C, cisplatin and hydroxyurea (HU). 23,25 PIDD deficiency also impaired PCNA monoubiquitination in response to these different agents, independently of the various cell lines used ( Figure 4D, Supplementary Figures S4A and S4B). …”

Section: Resultsmentioning

confidence: 99%

“…In keeping with this, inhibition of p21 degradation by the proteasome inhibitor MG132 completely inhibited PCNA monoubiquitination correlating with a sustained PCNA-p21 interaction ( Supplementary Figures S6A and B), which confirms that dissociation and degradation of p21 is necessary for PCNA monoubiquitination. 9,25,36 PIDD is a multifunctional protein, which is constitutively autoprocessed. Although the PIDD-C fragment triggers the RIP1-mediated NF-kB pathway, PIDD-CC sensitizes cells to apoptosis through recruitment of RAIDD/caspase-2.…”

Section: Discussionmentioning

confidence: 99%

“…23,24 Even though the effect of p21 on PCNA function is still controversial, several reports describe p21 as an inhibitor of PCNA monoubiquitination and thus TLS is induced by UV irradiation. 9,[25][26][27] PIDD (p53-induced protein with a death domain) was initially described as a p53-inducible gene. 28 PIDD contains N-terminal Leucine Rich Repeats (LRR), two intermediate ZU5 domains and a C-terminal Death Domain (DD).…”

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PIDD orchestrates translesion DNA synthesis in response to UV irradiation

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Schuepbach‐Mallepell²,

Eckert

et al. 2011

Cell Death Differ

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PIDD has been implicated in survival and apoptotic pathways in response to DNA damage, and a role for PIDD was recently identified in non-homologous end-joining (NHEJ) repair induced by c-irradiation. Here, we present an interaction of PIDD with PCNA, first identified in a proteomics screen. PCNA has essential functions in DNA replication and repair following UV irradiation. Translesion synthesis (TLS) is a process that prevents UV irradiation-induced replication blockage and is characterized by PCNA monoubiquitination and interaction with the TLS polymerase eta (polg). Both of these processes are inhibited by p21. We report that PIDD modulates p21-PCNA dissociation, and promotes PCNA monoubiquitination and interaction with polg in response to UV irradiation. Furthermore, PIDD deficiency leads to a defect in TLS that is associated, both in vitro and in vivo, with cellular sensitization to UV-induced apoptosis. Thus, PIDD performs key functions upon UV irradiation, including TLS, NHEJ, NF-jB activation and cell death. Cell Death and Differentiation (2011) 18, 1036-1045 doi:10.1038/cdd.2011; published online 18 March 2011 DNA lesions can result from endogenous metabolic processes as well as from exogenous DNA damaging agents. In both cases, different cellular responses are engaged (cell cycle arrest, repair pathways or apoptosis) to maintain genetic integrity. PCNA (proliferating cell nuclear antigen) acts as a DNA sliding clamp, which helps loading of replicative DNA polymerases. PCNA is involved in several forms of DNA repair, such as NER (nucleotide excision repair), BER (base excision repair) and MMR (mismatch repair), and also in other aspects of DNA metabolism, such as replication, chromatin assembly and cohesion. 1 PCNA mediates these different functions through interactions with proteins specific to each process. 2 Many of these PCNA interacting proteins (PIPs) contain a so-called PIP-box. 1,3 Competition between different partners for the same binding site on PCNA is one of the mechanisms that coordinate the functions of PCNA in DNA replication and repair. PCNA is loaded around the DNA by the conserved chaperone-like clamp loader complex RFC (replication factor C), consisting of five subunits (RFC1 to RFC5). 4,5 The RFC subunits all contain a PIP-box and thereby physically interact with PCNA. 6 Once PCNA is linked to the DNA, the RFC complex is ejected from the clamp to allow DNA polymerase access to the clamp. 7 The protein with the strongest affinity for PCNA is the PIPbox containing p21 (Cip1/Waf1), 8 a potent cyclin-dependent kinase (CDK) inhibitor involved in cell cycle regulation, except in response to UV, where cell cycle arrest is independent of p21. 9 P21 binds to PCNA and inhibits its activity, 10,11 mainly because p21 obstructs the interaction of PCNA with DNA replication and repair factors. [12][13][14][15] In vitro studies have shown that p21 also inhibits the loading of PCNA onto DNA, 7 thereby compromising DNA repair. 9 UV is one of the major exogenous sources of DNA damage. The most common...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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PIDD orchestrates translesion DNA synthesis in response to UV irradiation

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Schuepbach‐Mallepell²,

Eckert

et al. 2011

Cell Death Differ

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“…16,17 It is possible that this association, which prevents the binding of p21 cip1 to PCNA, 17 may lead to p21 efficient ubiquitindependent degradation, an essential event for optimal DNA repair through PCNA function. 19 Indeed, recent studies in various cellular models clearly show that downregulation or degradation of p21 after low doses of UV irradiation is required to allow proper DNA repair, [20][21][22][23] whereas a nondegradable mutant of p21 is able to efficiently block this process. 19 Conversely, overexpression of p21 cip1 is able to inhibit, by competing for the same PCNA-binding domain (PIP domain), the association of p15 PAF with PCNA.…”

Section: Discussionmentioning

confidence: 99%

ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress

et al. 2009

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After genotoxic stress, normal cells trigger DNA repair or, if unable to repair, undergo apoptosis to eradicate the cells that bear the risk of becoming tumorigenic. Here we show that repression of the transcription factor, activating transcription factor 3 (ATF3), after ultraviolet (UV)-mediated genotoxic stress impairs the DNA repair process. We provide evidence that ATF3 directly regulates the proliferating cell nuclear antigen (PCNA)-associated factor KIAA0101/p15 PAF . We further show that the expressions of ATF3 and p15 PAF is sufficient to trigger the DNA repair machinery, and that attenuation of their expression alters DNA repair mechanisms. We show that the expression of p15 PAF compensates for a lack of ATF3 expression, thereby constituting a major effector of ATF3 in the DNA repair process. In addition, we provide evidence that p15 PAF expression is required for the correct function of PCNA during DNA repair, as prevention of their interaction significantly alters DNA repair mechanisms. Finally, defective DNA repair, because of the downregulation of p15 PAF expression, rendered the cells more sensitive to UV-induced cell death. Therefore, our results suggest ATF3 and p15 PAF as novel gatekeepers of genomic integrity after UV exposure. Environmental genotoxic stress is one of the major causes of genomic instability. During such a stress, the maintenance of genomic integrity is of crucial importance to allow correct cellular function. The nucleotide excision repair (NER) machinery is responsible for recognition and incision of DNA lesions caused by ultraviolet (UV) irradiation and chemical agents. 1 Proliferating cell nuclear antigen (PCNA) is responsible for recruitment of Pold and, therefore, mediates DNA resynthesis within the site of the lesion. 1 The importance of such machinery is underscored by the numerous human syndromes, such as xeroderma pigmentosum (XP) and trichothiodystrophy (TTD), caused by the mutation of genes involved in DNA repair. Such mutations compromise genomic integrity, and XP and TTD patients are highly photosensitive and prone to develop skin tumors of keratinocyte origin, such as basal and squamous cell carcinoma. Severe defects in the DNA repair mechanism thus impair the apoptotic pathway responsible for destruction of cells that bear the risk of becoming tumorigenic. The correct DNA damage response is therefore of great importance in the maintenance of a UV-inducible anticancer barrier that elicits growth arrest, repair or cell death.Activating transcription factor 3 (ATF3) is a member of the ATF/CREB subfamily of the basic region leucine zipper (bZIP) family and may be strongly induced in a variety of tissues by different stress signals. 2 Several pathways are responsible for ATF3 induction, such as ATM and Nibrin 1, JNK and NF-kB, in a p53-dependent or -independent manner. 3-5 Induction of ATF3 often correlates with cellular damage, suggesting an important role during the cellular stress response. 6 We have recently reported that the alteration of Egr-1 expression during ...

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“…p21 downregulation is required for efficient ubiquitination of PCNA as well as the interaction of the PCNA-Pol h interaction [Soria et al, 2006] and the assembly of Pol h foci after UV irradiation [Soria et al, 2008]. Much further work needs to be done to understand the interplay between the changes in p12 and p21, in terms of how this affects DNA replication in unperturbed S-phase cells and in cells where DNA damage triggers the activation of p53 to the point where p21 is highly expressed.…”

Section: Connections Between P12 and P21çp21as A Regulator Of Pol D Amentioning

confidence: 99%

Regulation of human DNA polymerase delta in the cellular responses to DNA damage

Lee

Zhang

Lin

et al. 2012

Environ and Mol Mutagen

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The p12 subunit of polymerase delta (Pol d) is degraded in response to DNA damage induced by UV, alkylating agents, oxidative, and replication stresses. This leads to the conversion of the Pol d4 holoenzyme to the heterotrimer, Pol d3. We review studies that establish that Pol d3 formation is an event that could have a major impact on cellular processes in genomic surveillance, DNA replication, and DNA repair. p12 degradation is dependent on the apical ataxia telangiectasia and Rad3 related (ATR) kinase and is mediated by the ubiquitin-proteasome system. Pol d3 exhibits properties of an ''antimutator'' polymerase, suggesting that it could contribute to an increased surveillance against mutagenesis, for example, when Pol d carries out bypass synthesis past small base lesions that engage in spurious base pairing. Chromatin immunoprecipitation analysis and examination of the spatiotemporal recruitment of Pol d to sites of DNA damage show that Pol d3 is the primary form of Pol d associated with cyclobutane pyrimidine dimer lesions and therefore should be considered as the operative form of Pol d engaged in DNA repair. We propose a model for the switching of Pol d with translesion polymerases, incorporating the salient features of the recently determined structure of monoubiquitinated proliferating cell nuclear antigen and emphasizing the role of Pol d3. Because of the critical role of Pol d activity in DNA replication and repair, the formation of Pol d3 in response to DNA damage opens the prospect that pleiotropic effects may ensue. This opens the horizons for future exploration of how this novel response to DNA damage contributes to genomic stability. Environ. Mol. Mutagen. 53:683-698, 2012. V V C 2012 Wiley Periodicals, Inc.

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P21Cip1/WAF1 downregulation is required for efficient PCNA ubiquitination after UV irradiation

Cited by 98 publications

References 53 publications

PIDD orchestrates translesion DNA synthesis in response to UV irradiation

PIDD orchestrates translesion DNA synthesis in response to UV irradiation

ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress

Regulation of human DNA polymerase delta in the cellular responses to DNA damage

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