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Simultaneous disruption of two DNA polymerases, Pol? and Pol?, in Avian DT40 cells unmasks the role of Pol? in cellular response to various DNA lesions

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posted on 2023-06-07, 15:35 authored by Kouji Hirota, Eiichiro Sonoda, Takuo Kawamoto, Akira Motegi, Chikahide Masutani, Fumio Hanaoka, Dávid Szüts, Shigenori Iwai, Julian E Sale, Alan LehmannAlan Lehmann, Shunichi Takeda
Replicative DNA polymerases are frequently stalled by DNA lesions. The resulting replication blockage is released by homologous recombination (HR) and translesion DNA synthesis (TLS). TLS employs specialized TLS polymerases to bypass DNA lesions. We provide striking in vivo evidence of the cooperation between DNA polymerase ?, which is mutated in the variant form of the cancer predisposition disorder xeroderma pigmentosum (XP-V), and DNA polymerase ? by generating POL?-/-/POL?-/- cells from the chicken DT40 cell line. POL?-/- cells are hypersensitive to a very wide range of DNA damaging agents, whereas XP-V cells exhibit moderate sensitivity to ultraviolet light (UV) only in the presence of caffeine treatment and exhibit no significant sensitivity to any other damaging agents. It is therefore widely believed that Pol? plays a very specific role in cellular tolerance to UV-induced DNA damage. The evidence we present challenges this assumption. The phenotypic analysis of POL?-/-/POL?-/- cells shows that, unexpectedly, the loss of Pol? significantly rescued all mutant phenotypes of POL?-/- cells and results in the restoration of the DNA damage tolerance by a backup pathway including HR. Taken together, Pol? contributes to a much wide range of TLS events than had been predicted by the phenotype of XP-V cells.

History

Publication status

  • Published

File Version

  • Published version

Journal

PLoS Genetics

ISSN

1553-7390

Publisher

Public Library of Science

Issue

10

Volume

6

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Notes

GDSC332

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2010-11-04

First Open Access (FOA) Date

2017-12-01

First Compliant Deposit (FCD) Date

2019-07-02

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