scholarly journals Effective mismatch repair depends on timely control of PCNA retention on DNA by the Elg1 complex

2019 ◽  
Vol 47 (13) ◽  
pp. 6826-6841 ◽  
Author(s):  
Lovely Jael Paul Solomon Devakumar ◽  
Christl Gaubitz ◽  
Victoria Lundblad ◽  
Brian A Kelch ◽  
Takashi Kubota
Keyword(s):  
Mismatch Repair ◽  
Mutation Rate ◽  
Proliferating Cell Nuclear Antigen ◽  
Nuclear Antigen ◽  
Mutator Phenotype ◽  
Sliding Clamp ◽  
Epistasis Analysis ◽  
Independent Process ◽  
Mismatch Recognition ◽  
Proliferating Cell

Abstract Proliferating cell nuclear antigen (PCNA) is a sliding clamp that acts as a central co-ordinator for mismatch repair (MMR) as well as DNA replication. Loss of Elg1, the major subunit of the PCNA unloader complex, causes over-accumulation of PCNA on DNA and also increases mutation rate, but it has been unclear if the two effects are linked. Here we show that timely removal of PCNA from DNA by the Elg1 complex is important to prevent mutations. Although premature unloading of PCNA generally increases mutation rate, the mutator phenotype of elg1Δ is attenuated by PCNA mutants PCNA-R14E and PCNA-D150E that spontaneously fall off DNA. In contrast, the elg1Δ mutator phenotype is exacerbated by PCNA mutants that accumulate on DNA due to enhanced electrostatic PCNA–DNA interactions. Epistasis analysis suggests that PCNA over-accumulation on DNA interferes with both MMR and MMR-independent process(es). In elg1Δ, over-retained PCNA hyper-recruits the Msh2–Msh6 mismatch recognition complex through its PCNA-interacting peptide motif, causing accumulation of MMR intermediates. Our results suggest that PCNA retention controlled by the Elg1 complex is critical for efficient MMR: PCNA needs to be on DNA long enough to enable MMR, but if it is retained too long it interferes with downstream repair steps.

scholarly journals Distinct Structural Alterations in Proliferating Cell Nuclear Antigen Block DNA Mismatch Repair

Biochemistry ◽  
2013 ◽  
Vol 52 (33) ◽  
pp. 5611-5619 ◽  
Author(s):  
Lynne M. Dieckman ◽  
Elizabeth M. Boehm ◽  
Manju M. Hingorani ◽  
M. Todd Washington
Keyword(s):  
Mismatch Repair ◽  
Proliferating Cell Nuclear Antigen ◽  
Dna Mismatch Repair ◽  
Nuclear Antigen ◽  
Structural Alterations ◽  
Dna Mismatch ◽  
Proliferating Cell

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

2015 ◽  
Vol 112 (18) ◽  
pp. 5667-5672 ◽  
Author(s):  
Janice Ortega ◽  
Jessie Y. Li ◽  
Sanghee Lee ◽  
Dan Tong ◽  
Liya Gu ◽  
...  
Keyword(s):  
Dna Replication ◽  
Dna Synthesis ◽  
Mismatch Repair ◽  
Posttranslational Modifications ◽  
Growth Factor Receptor ◽  
Nuclear Antigen ◽  
Dna Mismatch ◽  
Epidermal Growth ◽  
Mismatch Recognition ◽  
Proliferating Cell

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.

scholarly journals Differential Requirement for Proliferating Cell Nuclear Antigen in 5′ and 3′ Nick-directed Excision in Human Mismatch Repair

2004 ◽  
Vol 279 (17) ◽  
pp. 16912-16917 ◽  
Author(s):  
Shuangli Guo ◽  
Steven R. Presnell ◽  
Fenghua Yuan ◽  
Yanbin Zhang ◽  
Liya Gu ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Proliferating Cell Nuclear Antigen ◽  
Nuclear Antigen ◽  
Proliferating Cell

scholarly journals DNA Polymerases BI and D from the Hyperthermophilic Archaeon Pyrococcus furiosus Both Bind to Proliferating Cell Nuclear Antigen with Their C-Terminal PIP-Box Motifs

2007 ◽  
Vol 189 (15) ◽  
pp. 5652-5657 ◽  
Author(s):  
Kazuo Tori ◽  
Megumi Kimizu ◽  
Sonoko Ishino ◽  
Yoshizumi Ishino
Keyword(s):  
Dna Synthesis ◽  
Proliferating Cell Nuclear Antigen ◽  
Pyrococcus Furiosus ◽  
Dna Polymerases ◽  
Nuclear Antigen ◽  
Hyperthermophilic Archaeon ◽  
Sliding Clamp ◽  
Replication Fork Progression ◽  
Proliferating Cell

ABSTRACT Proliferating cell nuclear antigen (PCNA) is the sliding clamp that is essential for the high processivity of DNA synthesis during DNA replication. Pyrococcus furiosus, a hyperthermophilic archaeon, has at least two DNA polymerases, polymerase BI (PolBI) and PolD. Both of the two DNA polymerases interact with the archaeal P. furiosus PCNA (PfuPCNA) and perform processive DNA synthesis in vitro. This phenomenon, in addition to the fact that both enzymes display 3′-5′ exonuclease activity, suggests that both DNA polymerases work in replication fork progression. We demonstrated here that both PolBI and PolD functionally interact with PfuPCNA at their C-terminal PIP boxes. The mutant PolBI and PolD enzymes lacking the PIP-box sequence do not respond to the PfuPCNA at all in an in vitro primer extension reaction. This is the first experimental evidence that the PIP-box motif, located at the C termini of the archaeal DNA polymerases, is actually critical for PCNA binding to form a processive DNA-synthesizing complex.

scholarly journals Control of PCNA deubiquitylation in yeast

2010 ◽  
Vol 38 (1) ◽  
pp. 104-109 ◽  
Author(s):  
Alfonso Gallego-Sánchez ◽  
Francisco Conde ◽  
Pedro San Segundo ◽  
Avelino Bueno
Keyword(s):  
Dna Damage ◽  
Crucial Role ◽  
Proliferating Cell Nuclear Antigen ◽  
Molecular Mechanisms ◽  
Damage Tolerance ◽  
Nuclear Antigen ◽  
Dna Damage Tolerance ◽  
Sliding Clamp ◽  
Evolutionarily Conserved ◽  
Proliferating Cell

Eukaryotes ubiquitylate the replication factor PCNA (proliferating-cell nuclear antigen) so that it tolerates DNA damage. Although, in the last few years, the understanding of the evolutionarily conserved mechanism of ubiquitylation of PCNA, and its crucial role in DNA damage tolerance, has progressed impressively, little is known about the deubiquitylation of this sliding clamp in most organisms. In the present review, we will discuss potential molecular mechanisms regulating PCNA deubiquitylation in yeast.

scholarly journals Stability of the human polymerase δ holoenzyme and its implications in lagging strand DNA synthesis

2016 ◽  
Vol 113 (13) ◽  
pp. E1777-E1786 ◽  
Author(s):  
Mark Hedglin ◽  
Binod Pandey ◽  
Stephen J. Benkovic
Keyword(s):  
Dna Polymerase ◽  
Proliferating Cell Nuclear Antigen ◽  
Nuclear Antigen ◽  
Okazaki Fragment ◽  
Sliding Clamp ◽  
Dna Lesion ◽  
The Stability ◽  
Proliferating Cell ◽  
Lagging Strand ◽  
Extreme Stability

In eukaryotes, DNA polymerase δ (pol δ) is responsible for replicating the lagging strand template and anchors to the proliferating cell nuclear antigen (PCNA) sliding clamp to form a holoenzyme. The stability of this complex is integral to every aspect of lagging strand replication. Most of our understanding comes fromSaccharomyces cerevisaewhere the extreme stability of the pol δ holoenzyme ensures that every nucleobase within an Okazaki fragment is faithfully duplicated before dissociation but also necessitates an active displacement mechanism for polymerase recycling and exchange. However, the stability of the human pol δ holoenzyme is unknown. We designed unique kinetic assays to analyze the processivity and stability of the pol δ holoenzyme. Surprisingly, the results indicate that human pol δ maintains a loose association with PCNA while replicating DNA. Such behavior has profound implications on Okazaki fragment synthesis in humans as it limits the processivity of pol δ on undamaged DNA and promotes the rapid dissociation of pol δ from PCNA on stalling at a DNA lesion.

scholarly journals Evidence for Involvement of Yeast Proliferating Cell Nuclear Antigen in DNA Mismatch Repair

1996 ◽  
Vol 271 (45) ◽  
pp. 27987-27990 ◽  
Author(s):  
Robert E. Johnson ◽  
Gopala K. Kovvali ◽  
Sami N. Guzder ◽  
Neelam S. Amin ◽  
Connie Holm ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Proliferating Cell Nuclear Antigen ◽  
Dna Mismatch Repair ◽  
Nuclear Antigen ◽  
Dna Mismatch ◽  
Proliferating Cell

scholarly journals A cell permeable bimane-constrained PCNA-interacting peptide

2021 ◽  
Author(s):  
Aimee Jade Horsfall ◽  
Beth A Vandborg ◽  
Zoya Kikhtyak ◽  
Denis Scanlon ◽  
Wayne D Tilley ◽  
...  
Keyword(s):  
Dna Replication ◽  
Therapeutic Target ◽  
Proliferating Cell Nuclear Antigen ◽  
Nuclear Antigen ◽  
Sliding Clamp ◽  
Dna Replication And Repair ◽  
A Cell ◽  
Proliferating Cell

The human sliding clamp protein known as Proliferating Cell Nuclear Antigen (PCNA) orchestrates DNA-replication and -repair and as such is an ideal therapeutic target for proliferative diseases, including cancer. Peptides...

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