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DNA Damage Tolerance and Translesion Synthesis

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The DNA Damage Response: Implications on Cancer Formation and Treatment

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Abstract

When the replication machinery encounters a DNA lesion, it is able to continue to replicate the DNA either by damage avoidance processes involving switching templates, or by translesion synthesis past the lesion using specialized DNA polymerases. Most of these polymerases are in the Y-family and have open structures that enable them to accommodate particular damaged bases in their active sites. Translesion synthesis can be error-free or error-prone and defective DNA polymerase η results in the variant form of the highly skin-cancer prone disorder xeroderma pigmentosum. Single-stranded regions of DNA exposed at sites of stalled replication forks trigger the ubiquitination of the sliding clamp protein proliferating cell nuclear antigen (PCNA). This increases the affinity of the Y-family polymerases for PCNA, as they all contain ubiquitin-binding domains, and provides a mechanism for the recruitment of these enzymes to stalled replication forks.

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Abbreviations

BP:

benzo[a]pyrene

CPD:

cyclobutane pyrimidine dimers

MMS:

methyl methanesulfonate

SHM:

somatic hypermutation

NER:

nucleotide excision repair

TLS:

Translesion synthesis

UV:

ultraviolet

XP:

xeroderma pigmentosum

XP-V:

xeroderma pigmentosum variant

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Acknowledgements

I am grateful to Julian Sale for helpful comments on the manuscript. Work in my laboratory is supported by the Medical Research Council, ESF Eurodyna programme and the European Community integrated project on DNA repair.

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  1. Genome Damage and Stability Centre, University of Sussex, BN1 9RQ, Brighton, Falmer, UK

    Alan R. Lehmann

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  1. Signal Transduction Laboratory, Queensland Institute of Medical Research, Herston Road 300, Herston, 4006, Australia

    Kum Kum Khanna

  2. Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel

    Yosef Shiloh

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Lehmann, A.R. (2009). DNA Damage Tolerance and Translesion Synthesis. In: Khanna, K., Shiloh, Y. (eds) The DNA Damage Response: Implications on Cancer Formation and Treatment. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-2561-6_10

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