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A Role for Polymerase ? in the Cellular Tolerance to Cisplatin-Induced Damage

journal contribution
posted on 2023-06-07, 13:53 authored by Mark R. Albertella, Catherine M. Green, Alan LehmannAlan Lehmann, Mark J. O'Connor
Mutation of the POLH gene encoding DNA polymerase ? (pol ?) causes the UV-sensitivity syndrome xeroderma pigmentosum-variant (XP-V) which is linked to the ability of pol ? to accurately bypass UV-induced cyclobutane pyrimidine dimers during a process termed translesion synthesis. Pol ? can also bypass other DNA damage adducts in vitro, including cisplatin-induced intrastrand adducts, although the physiological relevance of this is unknown. Here, we show that independent XP-V cell lines are dramatically more sensitive to cisplatin than the same cells complemented with functional pol ?. Similar results were obtained with the chemotherapeutic agents, carboplatin and oxaliplatin, thus revealing a general requirement for pol ? expression in providing tolerance to these platinum-based drugs. The level of sensitization observed was comparable to that of XP-A cells deficient in nucleotide excision repair, a recognized and important mechanism for repair of cisplatin adducts. However, unlike in XP-A cells, the absence of pol ? expression resulted in a reduced ability to overcome cisplatin-induced S phase arrest, suggesting that pol ? is involved in translesion synthesis past these replication-blocking adducts. Subcellular localization studies also highlighted an accumulation of nuclei with pol ? foci that correlated with the formation of monoubiquitinated proliferating cell nuclear antigen following treatment with cisplatin, reminiscent of the response to UV irradiation and further indicating a role for pol ? in dealing with cisplatin-induced damage. Together, these data show that pol ? represents an important determinant of cellular responses to cisplatin, which could have implications for acquired or intrinsic resistance to this key chemotherapeutic agent.

History

Publication status

  • Published

Journal

Cancer Research

ISSN

0008-5472

Publisher

American Association for Cancer Research

Issue

21

Volume

65

Page range

9799-806

Notes

0008-5472 Journal Article GDSC148

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2007-03-19

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