Distinct structural alterations in proliferating cell nuclear antigen block DNA mismatch repair

Lynne Dieckman, Elizabeth M. Boehm, Manju M. Hingorani, M. Todd Washington

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

During 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 MutSα-dependent MMR, and the C81R mutant PCNA protein partially blocks both MutSα-dependent and MutSβ-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 α-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 α-helices lining the central hole and this loop are both necessary to form productive complexes with MutSα and mismatch-containing DNA.

Original languageEnglish
Pages (from-to)5611-5619
Number of pages9
JournalBiochemistry
Volume52
Issue number33
DOIs
StatePublished - Aug 20 2013
Externally publishedYes

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DNA Mismatch Repair
Proliferating Cell Nuclear Antigen
Repair
DNA
Substitution reactions
Nuclear Proteins
Amino Acid Substitution
Linings
Amino Acids
Defects
Proteins
Structural integrity
Mutant Proteins
DNA Replication
Machinery
Crystal structure
X-Rays
X rays

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Medicine(all)

Cite this

Distinct structural alterations in proliferating cell nuclear antigen block DNA mismatch repair. / Dieckman, Lynne; Boehm, Elizabeth M.; Hingorani, Manju M.; Washington, M. Todd.

In: Biochemistry, Vol. 52, No. 33, 20.08.2013, p. 5611-5619.

Research output: Contribution to journalArticle

Dieckman, Lynne ; Boehm, Elizabeth M. ; Hingorani, Manju M. ; Washington, M. Todd. / Distinct structural alterations in proliferating cell nuclear antigen block DNA mismatch repair. In: Biochemistry. 2013 ; Vol. 52, No. 33. pp. 5611-5619.
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