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