PCNA trimer instability inhibits translesion synthesis by DNA polymerase η and by DNA polymerase δ

Lynne Dieckman, M. Todd Washington

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Translesion synthesis (TLS), the process by which DNA polymerases replicate through DNA lesions, is the source of most DNA damage-induced mutations. Sometimes TLS is carried out by replicative polymerases that have evolved to synthesize DNA on non-damaged templates. Most of the time, however, TLS is carried out by specialized translesion polymerases that have evolved to synthesize DNA on damaged templates. TLS requires the mono-ubiquitylation of the replication accessory factor proliferating cell nuclear antigen (PCNA). PCNA and ubiquitin-modified PCNA (UbPCNA) stimulate TLS by replicative and translesion polymerases. Two mutant forms of PCNA, one with an E113G substitution and one with a G178S substitution, support normal cell growth but inhibit TLS thereby reducing mutagenesis in yeast. A re-examination of the structures of both mutant PCNA proteins revealed substantial disruptions of the subunit interface that forms the PCNA trimer. Both mutant proteins have reduced trimer stability with the G178S substitution causing a more severe defect. The mutant forms of PCNA and UbPCNA do not stimulate TLS of an abasic site by either replicative Pol δ or translesion Pol η. Normal replication by Pol η was also impacted, but normal replication by Pol δ was much less affected. These findings support a model in which reduced trimer stability causes these mutant PCNA proteins to occasionally undergo conformational changes that compromise their ability to stimulate TLS by both replicative and translesion polymerases.

Original languageEnglish
Pages (from-to)367-376
Number of pages10
JournalDNA Repair
Volume12
Issue number5
DOIs
StatePublished - May 1 2013
Externally publishedYes

Fingerprint

Proliferating Cell Nuclear Antigen
DNA-Directed DNA Polymerase
Substitution reactions
DNA
Nuclear Proteins
Ubiquitin
Mutagenesis
Ubiquitination
Accessories
Cell growth
Mutant Proteins
Yeast
DNA Damage
Proteins
Yeasts
Defects
Mutation
Growth

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

PCNA trimer instability inhibits translesion synthesis by DNA polymerase η and by DNA polymerase δ. / Dieckman, Lynne; Washington, M. Todd.

In: DNA Repair, Vol. 12, No. 5, 01.05.2013, p. 367-376.

Research output: Contribution to journalArticle

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