Filling gaps in translesion DNA synthesis in human cells

Annabel Quinet, Leticia K. Lerner, Davi J. Martins, Carlos F.M. Menck

Research output: Contribution to journalShort surveypeer-review

7 Scopus citations

Abstract

During DNA replication, forks may encounter unrepaired lesions that hamper DNA synthesis. Cells have universal strategies to promote damage bypass allowing cells to survive. DNA damage tolerance can be performed upon template switch or by specialized DNA polymerases, known as translesion (TLS) polymerases. Human cells count on more than eleven TLS polymerases and this work reviews the functions of some of these enzymes: Rev1, Pol η Pol ι Pol κ Pol θ and Pol ζ. The mechanisms of damage bypass vary according to the lesion, as well as to the TLS polymerases available, and may occur directly at the fork during replication. Alternatively, the lesion may be skipped, leaving a single-stranded DNA gap that will be replicated later. Details of the participation of these enzymes are revised for the replication of damaged template. TLS polymerases also have functions in other cellular processes. These include involvement in somatic hypermutation in immunoglobulin genes, direct participation in recombination and repair processes, and contributing to replicating noncanonical DNA structures. The importance of DNA damage replication to cell survival is supported by recent discoveries that certain genes encoding TLS polymerases are induced in response to DNA damaging agents, protecting cells from a subsequent challenge to DNA replication. We retrace the findings on these genotoxic (adaptive) responses of human cells and show the common aspects with the SOS responses in bacteria. Paradoxically, although TLS of DNA damage is normally an error prone mechanism, in general it protects from carcinogenesis, as evidenced by increased tumorigenesis in xeroderma pigmentosum variant patients, who are deficient in Pol η. As these TLS polymerases also promote cell survival, they constitute an important mechanism by which cancer cells acquire resistance to genotoxic chemotherapy. Therefore, the TLS polymerases are new potential targets for improving therapy against tumors.

Original languageEnglish
Pages (from-to)127-142
Number of pages16
JournalMutation Research - Genetic Toxicology and Environmental Mutagenesis
Volume836
DOIs
StatePublished - Dec 2018

Keywords

  • Chemotherapy
  • DNA damage
  • DNA replication
  • Damage bypass
  • Gap filling
  • Genotoxic adaptive responses
  • Pyrimidine dimer
  • SOS responses
  • Tolerance mechanisms
  • Translesion polymerases
  • Ultraviolet

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