DNA Polymerase η, a Key Protein in Translesion Synthesis in Human Cells

  • Séverine Cruet-Hennequart
  • Kathleen Gallagher
  • Anna M. Sokòl
  • Sangamitra Villalan
  • Áine M. Prendergast
  • Michael P. Carty
Chapter
Part of the Subcellular Biochemistry book series (SCBI, volume 50)

Abstract

Genomic DNA is constantly damaged by exposure to exogenous and endogenous agents. Bulky adducts such as UV-induced cyclobutane pyrimidine dimers (CPDs) in the template DNA present a barrier to DNA synthesis by the major eukaryotic replicative polymerases including DNA polymerase δ. Translesion synthesis (TLS) carried out by specialized DNA polymerases is an evolutionarily conserved mechanism of DNA damage tolerance. The Y family of DNA polymerases, including DNA polymerase η (Pol η), the subject of this chapter, play a key role in TLS. Mutations in the human POLH gene encoding Pol η underlie the genetic disease xeroderma pigmentosum variant (XPV), characterized by sun sensitivity, elevated incidence of skin cancer, and at the cellular level, by delayed replication and hypermutability after UV-irradiation. Pol η is a low fidelity enzyme when copying undamaged DNA, but can carry out error-free TLS at sites of UV-induced dithymine CPDs. The active site of Pol η has an open conformation that can accommodate CPDs, as well as cisplatin-induced intrastrand DNA crosslinks. Pol η is recruited to sites of replication arrest in a tightly regulated process through interaction with PCNA. Pol η-deficient cells show strong activation of downstream DNA damage responses including ATR signaling, and accumulate strand breaks as a result of replication fork collapse. Thus, Pol η plays an important role in preventing genome instability after UV- and cisplatin-induced DNA damage. Inhibition of DNA damage tolerance pathways in tumors might also represent an approach to potentiate the effects of DNA damaging agents such as cisplatin.

Keywords

DNA polymerase eta Translesion synthesis XPV UV Cisplatin DDR 

Abbreviations

ATM

ataxia-telangiectasia mutated

ATR

ATM and Rad3-related

ATRIP

ATR-interacting protein

CPD

cyclobutane pyrimidine dimer

DDR

DNA damage response

DNA-PK

DNA-dependent protein kinase

Pol η

DNA polymerase eta

RPA

replication protein A

XPV

xeroderma pigmentosum variant

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Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Séverine Cruet-Hennequart
    • 1
  • Kathleen Gallagher
    • 1
  • Anna M. Sokòl
    • 2
  • Sangamitra Villalan
    • 2
  • Áine M. Prendergast
    • 3
  • Michael P. Carty
    • 1
  1. 1.Centre for Chromosome Biology, School of Natural SciencesNational University of Ireland, GalwayGalwayIreland
  2. 2.DNA Damage Response Laboratory, Biochemistry, School of Natural SciencesNational University of Ireland, GalwayGalwayIreland
  3. 3.Centre for Chromosome Biology, School of Natural SciencesNational University of Ireland, GalwayGalwayIreland

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