Oncogenic H-Ras Signaling Differentially Targets Replicative and Specialized DNA Polymerases for Depletion

Oncogene activation significantly alters DNA replication dynamics, causing replication stress and genome instability. However, little is known about DNA polymerase expression and regulation during oncogene-induced replication stress. We discovered that the Pol α catalytic subunit, Pol δ, Pol η and Pol κ are all depleted in response to H-Ras G12V overexpression in multiple human cell lines. Distinct transcriptional and post-translational mechanisms mediate replicative and specialized DNA polymerase regulation, respectively, and include both MEK-dependent and -independent pathways. Moreover, Pol η depletion is sufficient to induce a senescence-like growth arrest in non-transformed cells. We provide evidence that H-Ras G12V -induced polymerase depletion contributes not only to oncogene-induced replication stress, but also to cell cycle checkpoint enforcement. Polymerase degradation is a protective response, associated with improved cell survival in the face of oncogene-induced stress. Our findings significantly impact our understanding of oncogene-induced cellular transformation and suggest that imbalanced polymerase levels may contribute to neoplastic progression.