Fenofibrate triggers apoptosis of glioblastoma cells in vitro

The rapid accumulation of signaling and repair factors in the vicinity of DNA lesions is an integral part of the cellular DNA damage response (DDR) to DNA double-strand breaks (DSBs).1,2 This is initiated by posttranslational modifications of core histones, to which various effector proteins bind. The priming modification is ATM-mediated phosphorylation of histone H2AX at Ser-139 (γ-H2AX), a mark that exclusively decorates nuclear sites of DNA damage.2,3 Subsequently, accumulation of repair factors such as 53BP1 and the BRCA1 A complex impinges on the formation of K63-linked ubiquitin chains on histones H2A and H2AX, catalyzed in a sequential manner by the DNA damage-responsive E3 ubiquitin ligases RNF8 and RNF168. First, recruitment of RNF8 to DSB sites triggers initial Ubc13-dependent K63linked ubiquitylation of H2A-type histones, generating landing pads for another E3 ligase, RNF168, which also acts in conjunction with Ubc13 to amplify and spread polyubiquitylation of H2A-type histones to levels sufficient to allow sustained retention of repair factors at the damaged chromatin.1,4,5 These insights have given rise to the exciting concept of a DNA damage-specific “histone code,” a series of sequential histone modifications that uniquely demarcate sites of DNA damage, distinguishing them from other chromatin landscapes. Such a concept is widely accepted for many transcriptional processes, where propagation of several inter-dependent histone marks are required to activate transcription at specific gene promoters.6 Despite impressive advances in our understanding of the molecular underpinnings of DSB-associated chromatin ubiquitylation, one fundamental aspect of the DSB-specific histone code that has remained elusive is the actual site(s) of RNF8/RNF168-mediated ubiquitylation on H2A-type histones. in a previous issue of Cell Cycle, Penengo and coworkers provide important new insight into this Cell Cycle News & Views