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[Cancer Research 65, 9799-9806, November 1, 2005]
© 2005 American Association for Cancer Research

Cell and Tumor Biology

A Role for Polymerase {eta} in the Cellular Tolerance to Cisplatin-Induced Damage

Mark R. Albertella1, Catherine M. Green2, Alan R. Lehmann2 and Mark J. O'Connor1

1 KuDOS Pharmaceuticals Ltd., Cambridge Science Park, Cambridge and 2 Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton, United Kingdom

Requests for reprints: Mark J. O'Connor, KuDOS Pharmaceuticals Ltd., 327 Cambridge Science Park, Milton Road, Cambridge, CB4 OWG, United Kingdom. Phone: 44-1223-434733; Fax: 44-1223-719720; E-mail: mjoconnor{at}kudospharma.co.uk.

Mutation of the POLH gene encoding DNA polymerase {eta} (pol {eta}) causes the UV-sensitivity syndrome xeroderma pigmentosum-variant (XP-V) which is linked to the ability of pol {eta} to accurately bypass UV-induced cyclobutane pyrimidine dimers during a process termed translesion synthesis. Pol {eta} 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 {eta}. Similar results were obtained with the chemotherapeutic agents, carboplatin and oxaliplatin, thus revealing a general requirement for pol {eta} 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 {eta} expression resulted in a reduced ability to overcome cisplatin-induced S phase arrest, suggesting that pol {eta} is involved in translesion synthesis past these replication-blocking adducts. Subcellular localization studies also highlighted an accumulation of nuclei with pol {eta} 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 {eta} in dealing with cisplatin-induced damage. Together, these data show that pol {eta} represents an important determinant of cellular responses to cisplatin, which could have implications for acquired or intrinsic resistance to this key chemotherapeutic agent.




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Copyright © 2005 by the American Association for Cancer Research.