RB Restricts DNA Damage-Initiated Tumorigenesis through an LXCXE-Dependent Mechanism of Transcriptional Control

Abstract

The LXCXE peptide motif facilitates interaction between the RB tumor suppressor and a large number of cellular proteins that are expected to impinge on diverse biological processes. Invitro and invivo analyses demonstrated that LXCXE binding function is dispensable for RB promoter association and control of basal gene expression. Dependence on this function of RB is unmasked after DNA damage, wherein LXCXE binding is essential for exerting control over E2F3 and suppressing cell-cycle progression in the presence of genotoxic stress. Gene expression profiling revealed that the transcriptional program coordinated by this specific aspect of RB is associated with progression of human hepatocellular carcinoma and poor disease outcome. Consistent with these findings, biological challenge revealeda requirement for LXCXE binding in suppression of genotoxin-initiated hepatocellular carcinoma invivo. Together, these studies establish an essential role ofthe LXCXE binding motif for RB-mediated transcriptional control, response to genotoxic insult, and tumor suppression.