Regulation of PCNA–protein interactions for genome stability

Mailand, Niels; Gibbs-Seymour, Ian; Bekker‐Jensen, Simon

doi:10.1038/nrm3562

Cited by 336 publications

(349 citation statements)

References 143 publications

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“…PCNA roles in these reactions appear to be regulated through posttranslational modifications such as ubiquitination, sumoylation, and phosphorylation. Although the role of PCNA ubiquitination and sumoylation is relatively well understood (40), little is known about the functional significance of PCNA phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

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Phosphorylation of PCNA by EGFR inhibits mismatch repair and promotes misincorporation during DNA synthesis

Ortega

Li²,

Lee

et al. 2015

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

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Proliferating cell nuclear antigen (PCNA) plays essential roles in eukaryotic cells during DNA replication, DNA mismatch repair (MMR), and other events at the replication fork. Earlier studies show that PCNA is regulated by posttranslational modifications, including phosphorylation of tyrosine 211 (Y211) by the epidermal growth factor receptor (EGFR). However, the functional significance of Y211-phosphorylated PCNA remains unknown. Here, we show that PCNA phosphorylation by EGFR alters its interaction with mismatch-recognition proteins MutSα and MutSβ and interferes with PCNA-dependent activation of MutLα endonuclease, thereby inhibiting MMR at the initiation step. Evidence is also provided that Y211-phosphorylated PCNA induces nucleotide misincorporation during DNA synthesis. These findings reveal a novel mechanism by which Y211-phosphorylated PCNA promotes cancer development and progression via facilitating error-prone DNA replication and suppressing the MMR function.is an essential genome stability pathway that removes mismatches introduced by nucleotide misincorporation during DNA replication (1-4). MMR in eukaryotic cells is nick-directed and targeted specifically to the newly synthesized DNA strand (5, 6). MMR is carried out in three phases: initiation, excision, and resynthesis. The initiation phase involves mismatch recognition by MutSα or MutSβ; assembly of the initiation complex containing MutSα (or MutSβ), MutLα, and proliferating cell nuclear antigen (PCNA); and localization of the strand discrimination signal (a single-strand nick) by this complex (7-11) in a process that is incompletely understood. During the excision phase, exonuclease 1 (Exo1) removes nascent DNA exonucleolytically from a distal nick to the mismatch in a reaction that requires MutSα (or MutSβ), MutLα, and PCNA. Replication protein A (RPA) stimulates DNA excision by Exo1 and protects single-stranded DNA from cleavage by nucleases (12, 13). During the resynthesis phase of MMR, DNA polymerase δ fills in the single-strand DNA gap left by DNA excision in a concerted reaction that requires replication factor C (RFC), PCNA, and RPA, followed by DNA ligase I-catalyzed nick ligation.Mutations or promoter hypermethylation in coding or regulatory regions of MMR genes MSH2, MSH6, MLH1, and PMS2 are linked to susceptibility to colorectal and other cancers in humans and other organisms (2, 14-16). The cellular phenotype associated with defects in MMR includes an elevated genomewide mutation rate as well as frequent changes in DNA microsatellite repeats, a phenomenon called microsatellite instability (MSI). Thus, MSI is frequently used as a biomarker for (or hallmark of) MMR deficiency (1-4). However, a significant number of MSIpositive tumors do not carry mutations in known MMR genes (17). Recent studies have shown that mutations affecting the proofreading nuclease activity of DNA polymerases δ and e are associated with some colorectal and/or endometrial cancers (18), and that defects in the gene encoding histone H3 Lys36 (H3K36) trimethyltran...

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Section: Discussionmentioning

confidence: 99%

“…PCNA orchestrates essentially all metabolic reactions at the replication fork, including DNA replication, MMR, and DNA translesion synthesis (37,40). PCNA roles in these reactions appear to be regulated through posttranslational modifications such as ubiquitination, sumoylation, and phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of PCNA by EGFR inhibits mismatch repair and promotes misincorporation during DNA synthesis

Ortega

Li²,

Lee

et al. 2015

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

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“…In the nucleus of the cell, the various PCNA ligands compete for binding to the three protomers of the ring and there likely is a hierarchy based on relative affinities modulated by posttranslational modifications that, together with steric hindrance and relative protein concentrations, determine the occupancy of the PCNA protomers 30 . The simultaneous occupation of all three sites by identical ligands, as seen here and in other quantitative binding studies, may not be the prevalent situation inside the cell.…”

Section: Discussionmentioning

confidence: 99%

Structure of p15PAF–PCNA complex and implications for clamp sliding during DNA replication and repair

et al. 2015

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The intrinsically disordered protein p15 PAF regulates DNA replication and repair by binding to the proliferating cell nuclear antigen (PCNA) sliding clamp. We present the structure of the human p15 PAF -PCNA complex. Crystallography and NMR show the central PCNA-interacting protein motif (PIP-box) of p15 PAF tightly bound to the front-face of PCNA. In contrast to other PCNA-interacting proteins, p15 PAF also contacts the inside of, and passes through, the PCNA ring. The disordered p15 PAF termini emerge at opposite faces of the ring, but remain protected from 20S proteasomal degradation. Both free and PCNA-bound p15 PAF binds DNA mainly through its histone-like N-terminal tail, while PCNA does not, and a model of the ternary complex with DNA inside the PCNA ring is consistent with electron micrographs. We propose that p15 PAF acts as a flexible drag that regulates PCNA sliding along the DNA and facilitates the switch from replicative to translesion synthesis polymerase binding.

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“…TLS polymerases have large and flexible active sites that can accommodate a range of bulky nucleobase adducts such as exocyclic lesions, cyclobutane dimers, and DNA-DNA cross-links. However, DNA synthesis by TLS polymerases is inherently inefficient and error-prone, probably due to the expanded size and flexibility of their active sites and the lack of 3Ј 3 5Ј-proofreading activity (19,20).…”

Section: Dna-protein Cross-links (Dpcs)mentioning

confidence: 99%

Error-prone Translesion Synthesis Past DNA-Peptide Cross-links Conjugated to the Major Groove of DNA via C5 of Thymidine

Wickramaratne

Boldry²,

Buehler

et al. 2015

Journal of Biological Chemistry

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Background: DNA-protein conjugates can be induced by reactive oxygen species and proteolytically cleaved to the corresponding peptide conjugates. Results: Polymerase bypass past C5-dT peptide conjugates catalyzed by human polymerases and gives rise to base substitutions and deletions. Conclusion: Replication past C5-T peptide conjugates is mutagenic. Significance: This study provides the first evidence for error-prone replication of DPCs cross-linked to pyrimidines in DNA.

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Regulation of PCNA–protein interactions for genome stability

Cited by 336 publications

References 143 publications

Phosphorylation of PCNA by EGFR inhibits mismatch repair and promotes misincorporation during DNA synthesis

Phosphorylation of PCNA by EGFR inhibits mismatch repair and promotes misincorporation during DNA synthesis

Structure of p15PAF–PCNA complex and implications for clamp sliding during DNA replication and repair

Error-prone Translesion Synthesis Past DNA-Peptide Cross-links Conjugated to the Major Groove of DNA via C5 of Thymidine

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