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Growth of precancerous and cancer cells relies on their tolerance of oncogene-induced replication stress (RS). Translesion synthesis (TLS) plays an essential role in the cellular tolerance of various types of RS and bypasses replication barriers by employing specialized polymerases. However, limited information is available about the role of TLS polymerases in oncogene-induced RS. Here, we report that Polη, a Y-family TLS polymerase, promotes cellular tolerance of Myc-induced RS. Polη was recruited to Myc-induced RS sites, and Polη depletion enhanced the Myc-induced slowing and stalling of replication forks and the subsequent generation of double-strand breaks (DSBs). Overexpression of a catalytically dead Polη also promoted Myc-induced DSB formation. In the absence of Polη, Myc-induced DSB formation depended on MUS81-EME2 (the S-phase-specific endonuclease complex), and concomitant depletion of MUS81-EME2 and Polη enhanced RS and cell death in a synergistic manner. Collectively, these results indicate that Polη facilitates fork progression during Myc-induced RS, thereby helping cells tolerate the resultant deleterious effects. Additionally, the present study highlights the possibility of a synthetic sickness or lethality between Polη and MUS81-EME2 in cells experiencing Myc-induced RS.

Polη, a Y-family translesion synthesis polymerase, promotes cellular tolerance of Myc-induced replication stress