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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Filling gaps in translesion DNA synthesis in human cells

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Author(s):
Quinet, Annabel [1] ; Lerner, Leticia K. [2] ; Martins, Davi J. [3] ; Menck, Carlos F. M. [3]
Total Authors: 4
Affiliation:
[1] St Louis Univ, Sch Med, St Louis, MO 63103 - USA
[2] MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH - England
[3] Univ Sao Paulo, Inst Biomed Sci, Sao Paulo - Brazil
Total Affiliations: 3
Document type: Journal article
Source: MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS; v. 836, n. B, SI, p. 127-142, DEC 2018.
Web of Science Citations: 1
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 eta, Pol iota, Pol kappa, Pol theta and Pol zeta. 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 eta. As these us polymerases also promote cell survival, they constitute an important mechanism by which cancer cells acquire resistance to genotoxic chemotherapy. Therefore, the us polymerases are new potential targets for improving therapy against tumors. (AU)

FAPESP's process: 14/15982-6 - Consequences of repair deficiencies in damaged genome
Grantee:Carlos Frederico Martins Menck
Support type: Research Projects - Thematic Grants
FAPESP's process: 13/21075-9 - Participation of NADPH oxidase 2 induced by estrogen in the formation of DNA damage and autophagy regulation in breast cells
Grantee:Carlos Frederico Martins Menck
Support type: Research Grants - Visiting Researcher Grant - Brazil