A PolH Transcript with a Short 3'UTR Enhances PolH Expression and Mediates Cisplatin Resistance.

Platinum-based anticancer drugs are widely used as a first-line drug for cancers, such as non-small cell lung carcinoma (NSCLC) and bladder cancer. However, the efficacy is limited due to intrinsic or acquired resistance to these drugs. DNA polymerase eta (PolH, Polη) belongs to the Y-family of DNA polymerases and mediates DNA translesion synthesis, a major mechanism for DNA damage tolerance. Here, we showed that a high level of PolH is associated with cisplatin resistance in lung and bladder cancer. Consistent with this, loss of PolH markedly attenuates cisplatin resistance in both cisplatin-sensitive and cisplatin-resistant lung cancer cells. Interestingly, we found that due to the presence of multiple polyadenylation sites, alternative polyadenylation (APA) produces three major PolH transcripts with various lengths of 3'untranslated region (3'UTR; 427-/2516-/6245-nt). We showed that the short PolH transcript with 427-nt 3'UTR is responsible for high expression of PolH in various cisplatin-resistant lung and bladder cancer cell lines. Importantly, loss of the short PolH transcript significantly sensitizes cancer cells to cisplatin treatment. Moreover, we found that miR-619 selectively inhibits the ability of the long PolH transcript with 6245-nt 3'UTR to produce PolH protein and, subsequently, PolH-dependent cell growth. Together, our data suggest that PolH expression is controlled by APA and that the short PolH transcript produced by APA can escape miR-619-mediated repression and, subsequently, confers PolH-mediated cisplatin resistance. SIGNIFICANCE: A short PolH transcript produced by alternative polyadenylation escapes repression by miR-619 and confers resistance to cisplatin. ©2019 American Association for Cancer Research.