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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'ConnorMutation 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 ResearchISSN
0008-5472Publisher
American Association for Cancer ResearchPublisher URL
External DOI
Issue
21Volume
65Page range
9799-806Notes
0008-5472 Journal Article GDSC148Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2007-03-19Usage metrics
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