A chromatin-bound kinase, ERK8, protects genomic integrity by inhibiting HDM2-mediated degradation of the DNA clamp PCNA

Abstract

Proliferating cell nuclear antigen (PCNA) acts as a scaffold, coordinator, and stimulator of numerous processes required for faithful transmission of genetic information. Maintaining PCNA levels above a critical threshold is essential, but little is known about PCNA protein turnover. We now show that ERK8 (extracellular signal-regulated kinase 8) is required for PCNA protein stability. ERK8 contains a conserved PCNA-interacting protein (PIP) box. Chromatin-bound ERK8 (ERK8CHROMATIN) interacts via this motif with PCNACHROMATIN, which acts as a platform for numerous proteins involved in DNA metabolism. Silencing ERK8 decreases PCNA levels and increases DNA damage. Ectopic expression of PCNA blocks DNA damage induced by ERK8 loss. ERK8 prevents HDM2-mediated PCNA destruction by inhibiting the association of PCNA with HDM2. This regulation is physiologically relevant as ERK8 activity is inhibited in transformed mammary cells. Our results reveal an unanticipated mechanism to control PCNA levels in normal cycling mammary epithelial cells and implicate ERK8 in the regulation of genomic stability.