Transcriptional regulation and maintenance of genome stability by checkpoint kinase Chk1

Abstract

Eukaryotic cells are equipped with coordinated systems to contend with DNA damage, such as those which are used in cell cycle arrest, DNA repair, apoptosis and premature senescence to maintain genomic integrity. These systems are regulated at least in part by transcriptional activation or repression. Although processes to activate transcription of specific genes have been characterized in the context of sequence-specific DNA binding factors, mechanisms of transcriptional repression have been largely unexplored. Recently, we identified phosphorylation of histone H3-threonine 11 (H3-T11), a novel chromatin modification for transcriptional activation, that was rapidly reduced after DNA damage. We have begun to unravel the biological significance of H3-T11 phosphorylation in transcriptional regulation and uncovered a novel mechanism underlying DNA damage induced transcriptional repression. Namely, Chk1-release from chromatin and PP1 activation upon DNA damage cooperatively dephosphorylate H3-pT11 in response to DNA damage. We propose that the Chk1-dependent repression of cell cycle related genes may serve as a long term checkpoint arrest for DNA damage, leading cells with severe or unrepairable DNA damage to permanently exit from cell cycle.