CENP-A chromatin disassembly in stressed and senescent murine cells

Abstract

Centromeres are chromosomal domains essential for genomic stability. We report here the remarkable transcriptional and epigenetic perturbations at murine centromeres in genotoxic stress conditions. A strong and selective transcriptional activation of centromeric repeats is detected within hours. This is followed by disorganization of centromeres with striking delocalization of nucleosomal CENP-A, the key determinant of centromere identity and function, in a mechanism requiring active transcription of centromeric repeats, the DNA Damage Response (DDR) effector ATM and chromatin remodelers/histone chaperones. In the absence of p53 checkpoint, activated transcription of centromeric repeats and CENP-A delocalization do not occur and cells accumulate micronuclei indicative of genomic instability. In addition, activated transcription and loss of centromeres identity are features of permanently arrested senescent cells with persistent DDR activation. Together, these findings bring out cooperation between DDR effectors and loss of centromere integrity as a safeguard mechanism to prevent genomic instability in context of persistent DNA damage signalling.