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Structure of C81R Mutant PCNA Protein Defective in Mismatch RepairStructure of C81R Mutant PCNA Protein Defective in Mismatch Repair
Structural highlights
Publication Abstract from PubMedDuring DNA replication, mismatches and small loops in the DNA resulting from insertions or deletions are repaired by the mismatch repair (MMR) machinery. Proliferating cell nuclear antigen (PCNA) plays an important role in both mismatch-recognition and resynthesis stages of MMR. Previously, two mutant forms of PCNA were identified that cause defects in MMR with little, if any, other defects. The C22Y mutant PCNA protein completely blocks MutSalpha-dependent MMR, and the C81R mutant PCNA protein partially blocks both MutSalpha-dependent and MutSbeta-dependent MMR. In order to understand the structural and mechanistic basis by which these two amino acid substitutions in PCNA proteins block MMR, we solved the X-ray crystal structures of both mutant proteins and carried out further biochemical studies. We found that these amino acid substitutions lead to subtle, distinct structural changes in PCNA. The C22Y substitution alters the positions of the alpha-helices lining the central hole of the PCNA ring, whereas the C81R substitution creates a distortion in an extended loop near the PCNA subunit interface. We conclude that the structural integrity of the alpha-helices lining the central hole and this loop are both necessary to form productive complexes with MutSalpha and mismatch-containing DNA. Distinct structural alterations in proliferating cell nuclear antigen block DNA mismatch repair.,Dieckman LM, Boehm EM, Hingorani MM, Washington MT Biochemistry. 2013 Aug 20;52(33):5611-9. doi: 10.1021/bi400378e. Epub 2013 Aug 2. PMID:23869605[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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