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 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 The MutSα-Proliferating Cell Nuclear Antigen Interaction in Human DNA Mismatch Repair

2008 ◽  
Vol 283 (19) ◽  
pp. 13310-13319 ◽  
Author(s):  
Ravi R. Iyer ◽  
Timothy J. Pohlhaus ◽  
Sihong Chen ◽  
Gregory L. Hura ◽  
Leonid Dzantiev ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Proliferating Cell Nuclear Antigen ◽  
Dna Mismatch Repair ◽  
Nuclear Antigen ◽  
Dna Mismatch ◽  
Human Dna ◽  
Antigen Interaction ◽  
Proliferating Cell

scholarly journals Isolation and Characterization of New Proliferating Cell Nuclear Antigen (POL30) Mutator Mutants That Are Defective in DNA Mismatch Repair

2002 ◽  
Vol 22 (19) ◽  
pp. 6669-6680 ◽  
Author(s):  
Patrick J. Lau ◽  
Hernan Flores-Rozas ◽  
Richard D. Kolodner
Keyword(s):  
Amino Acid ◽  
Mismatch Repair ◽  
Proliferating Cell Nuclear Antigen ◽  
Dna Mismatch Repair ◽  
Nuclear Antigen ◽  
Dna Mismatch ◽  
Isolation And Characterization ◽  
Proliferating Cell

ABSTRACT A number of studies have suggested a role for proliferating cell nuclear antigen (PCNA) in DNA mismatch repair (MMR). However, the majority of mutations in the POL30 gene encoding PCNA that cause MMR defects also cause replication and other repair defects that contribute to the increased mutation rate caused by these mutations. Here, 20 new pol30 mutants were identified and screened for MMR and other defects, resulting in the identification of two mutations, pol30-201 and pol30-204, that appear to cause MMR defects but little if any other defects. The pol30-204 mutation altered an amino acid (C81R) in the monomer-monomer interface region and resulted in a partial general MMR defect and a defect in MSH2-MSH6 binding in vitro. The pol30-201 mutation altered an amino acid (C22Y) located on the surface of the PCNA trimer that slides over the DNA but did not cause a defect in MSH2-MSH6 binding in vitro. The pol30-201 mutation caused an intermediate mutator phenotype. However, the pol30-201 mutation caused almost a complete defect in the repair of AC and GT mispairs and only a small defect in the repair of a “+T” insertion, an effect similar to that caused by an msh6Δ mutation, indicating that pol30-201 primarily effects MSH6-dependent MMR. The chromosomal double mutant msh3-FF>AA msh6-FF>AA eliminating the conserved FF residues of the PCNA interacting motif of these proteins caused a small (<10%) defect in MMR but showed synergistic interactions with mutations in POL30, indicating that the FF>AA substitution may not eliminate PCNA interactions in vivo. These results indicate that the interaction between PCNA and MMR proteins is more complex than was previously appreciated.

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 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 Dynamic human MutSα–MutLα complexes compact mismatched DNA

2020 ◽  
Vol 117 (28) ◽  
pp. 16302-16312 ◽  
Author(s):  
Kira C. Bradford ◽  
Hunter Wilkins ◽  
Pengyu Hao ◽  
Zimeng M. Li ◽  
Bangchen Wang ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Proliferating Cell Nuclear Antigen ◽  
Nuclear Antigen ◽  
Dna Complexes ◽  
Force Microscopy ◽  
Dna Mismatch ◽  
Mismatched Dna ◽  
Atomic Force ◽  
Higher Eukaryotes ◽  
Proliferating Cell

DNA mismatch repair (MMR) corrects errors that occur during DNA replication. In humans, mutations in the proteins MutSα and MutLα that initiate MMR cause Lynch syndrome, the most common hereditary cancer. MutSα surveilles the DNA, and upon recognition of a replication error it undergoes adenosine triphosphate-dependent conformational changes and recruits MutLα. Subsequently, proliferating cell nuclear antigen (PCNA) activates MutLα to nick the error-containing strand to allow excision and resynthesis. The structure–function properties of these obligate MutSα–MutLα complexes remain mostly unexplored in higher eukaryotes, and models are predominately based on studies of prokaryotic proteins. Here, we utilize atomic force microscopy (AFM) coupled with other methods to reveal time- and concentration-dependent stoichiometries and conformations of assembling human MutSα–MutLα–DNA complexes. We find that they assemble into multimeric complexes comprising three to eight proteins around a mismatch on DNA. On the timescale of a few minutes, these complexes rearrange, folding and compacting the DNA. These observations contrast with dominant models of MMR initiation that envision diffusive MutS–MutL complexes that move away from the mismatch. Our results suggest MutSα localizes MutLα near the mismatch and promotes DNA configurations that could enhance MMR efficiency by facilitating MutLα nicking the DNA at multiple sites around the mismatch. In addition, such complexes may also protect the mismatch region from nucleosome reassembly until repair occurs, and they could potentially remodel adjacent nucleosomes.

scholarly journals Interaction of proliferating cell nuclear antigen with PMS2 is required for MutLα activation and function in mismatch repair

2017 ◽  
Vol 114 (19) ◽  
pp. 4930-4935 ◽  
Author(s):  
Jochen Genschel ◽  
Lyudmila Y. Kadyrova ◽  
Ravi R. Iyer ◽  
Basanta K. Dahal ◽  
Farid A. Kadyrov ◽  
...  
Keyword(s):  
Amino Acid ◽  
Mismatch Repair ◽  
Amino Acid Substitution ◽  
Proliferating Cell Nuclear Antigen ◽  
Nuclear Antigen ◽  
Endonuclease Domain ◽  
Substitution Mutations ◽  
Proliferating Cell

Eukaryotic MutLα (mammalian MLH1–PMS2 heterodimer; MLH1–PMS1 in yeast) functions in early steps of mismatch repair as a latent endonuclease that requires a mismatch, MutSα/β, and DNA-loaded proliferating cell nuclear antigen (PCNA) for activation. We show here that human PCNA and MutLα interact specifically but weakly in solution to form a complex of approximately 1:1 stoichiometry that depends on PCNA interaction with the C-terminal endonuclease domain of the MutLα PMS2 subunit. Amino acid substitution mutations within a PMS2 C-terminal 721QRLIAP motif attenuate or abolish human MutLα interaction with PCNA, as well as PCNA-dependent activation of MutLα endonuclease, PCNA- and DNA-dependent activation of MutLα ATPase, and MutLα function in in vitro mismatch repair. Amino acid substitution mutations within the corresponding yeast PMS1 motif (723QKLIIP) reduce or abolish mismatch repair in vivo. Coupling of a weak allele within this motif (723AKLIIP) with an exo1Δ null mutation, which individually confer only weak mutator phenotypes, inactivates mismatch repair in the yeast cell.

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