Direct Interaction of p21 with p50, the Small Subunit of Human DNA Polymerase Delta

Li, Hao; Xie, Bin; Rahmeh, Amal; Zhou, Yajing; Lee, Marietta Y.W.T.

doi:10.4161/cc.5.4.2425

Cited by 18 publications

(16 citation statements)

References 59 publications

(84 reference statements)

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“…A phosphomimetic mutant of Ser458 reconstituted in the Pol d4 holoenzyme exhibited defects in processive synthesis on M13 templates, consistent with a loss of function of the PIP-box [Rahmeh et al, 2012]. There has also been evidence for the association of cyclin/CDKs with Pol d from immunoaffinity chromatography and coimmunoprecipitation experiments, raising issues of whether cell-cycle-dependent phosphorylation by CDKs may affect Pol d activity [Loor et al, 1997;Wu et al, 1998;Li et al, 2006a].…”

Section: Regulation Of Pol D Activity By Protein Phosphorylationmentioning

confidence: 89%

“…Thus, this provided the earliest proposed mechanism for the direct inhibition of Pol d activity in response to DNA damage. p21 interacts with Pol d as well as to PCNA; this binding occurs via the p50 subunit [Liu et al, 2003;Li et al, 2006a]. p21 levels are transcriptionally upregulated by the activation of p53 in response to DNA damage [Soria and Gottifredi, 2010].…”

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

confidence: 99%

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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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Section: Regulation Of Pol D Activity By Protein Phosphorylationmentioning

confidence: 89%

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 ability of PCNA to interact with RNF8 was examined by overlay blotting with digoxigenin-PCNA as previously described. 40 Lane M, protein molecular weight markers; lane 1, glutathione-S-transferase (0.5 μg); lane 2, his-tagged RNF8 (0.5 μg). The specificity of the interaction is supported by the failure to observe signals for the molecular weight markers and for glutathione-S-transferase.…”

Section: Discussionmentioning

confidence: 99%

PCNA is ubiquitinated by RNF8

Zhang¹,

Chea²,

Xiao³

et al. 2008

Cell Cycle

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The ubiquitination of PCNA is an essential event in the operation of the DNA Damage Tolerance (DDT) pathway that is activated after DNA damage caused by UV or chemical agents during S-phase. This pathway allows the bypass of DNA damage by translesion synthesis that would otherwise cause replication fork stalling. PCNA is mono-ubiquitinated by Rad18-Rad6, and polyubiquitinated by Rad5-Ubc13/Uev1 in the DDT pathway. Mono-and polyubiquitination of PCNA are key processes in the translesion bypass and template switching sub-pathways of the DDT. DNA damage by IR causes DSBs, which trigger the DNA Damage Response (DDR). The ubiquitin ligase RNF8 has a critical role in the assembly of BRCA1 complexes at the DSBs in the DDR. We show that RNF8 readily mono-ubiquitinates PCNA in the presence of UbcH5c, and polyubiquitinates PCNA in the added presence of Ubc13/Uev1a. These reactions are the same as those performed by Rad18-Rad6 and Rad5-Ubc13. RNF8 depletion suppressed both UV and MNNG-stimulated mono-ubiquitination of PCNA, revealing that an RNF8-dependent pathway for PCNA ubiquitination is operative in vivo. These findings provide evidence that RNF8, a key E3 ligase in the DDR, may also play a role in the DDT.

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“…A specific possibility arises from the number of observations that p21 inhibits DNA replication and competes with Pol δ for PCNA, so that p21 degradation may be a mechanism for regulating the onset of DNA synthesis. [71][72][73][74] Further studies of the temporal aspects as well as of mechanistic aspects of the degradation of CRL4 Cdt2 substrates in reconstituted systems could reveal new regulatory aspects of CRL4…”

Section: 70mentioning

confidence: 99%

The tail that wags the dog: p12, the smallest subunit of DNA polymerase δ, is degraded by ubiquitin ligases in response to DNA damage and during cell cycle progression

Lee¹,

Zhang²,

Lin³

et al. 2013

Cell Cycle

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(2014) The tail that wags the dog: p12, the smallest subunit of DNA polymerase δ, is degraded by ubiquitin ligases in response to DNA damage and during cell cycle progression, Cell Cycle Cdt2 , participate in the DNA damage-induced degradation of p12. We discuss how these E3 ligases integrate the formation of Pol δ3 and ubiquitinated PCNA for DNA repair processes. CRL4Cdt2 partially degrades p12 during normal cell cycle progression, thereby generating Pol δ3 during S phase. This novel finding extends the current view of the role of Pol δ3 in DNA repair and leads to the hypothesis that it participates in DNA replication. The coordinated regulation of licensing factors and Pol δ3 by CRL4 Cdt2 now opens new avenues for control of DNA replication. A parallel study of Pol δ4 and Pol δ3 in Okazaki fragment processing provides evidence for a role of Pol δ3 in DNA replication. We discuss several new perspectives of the role of the 2 forms of Pol δ in DNA replication and repair, as well the significance of the integration of p12 regulation in DNA repair and cell cycle progression.

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Direct Interaction of p21 with p50, the Small Subunit of Human DNA Polymerase Delta

Cited by 18 publications

References 59 publications

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

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

PCNA is ubiquitinated by RNF8

The tail that wags the dog: p12, the smallest subunit of DNA polymerase δ, is degraded by ubiquitin ligases in response to DNA damage and during cell cycle progression

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