Checkpoint kinases regulate the circadian clock after DNA damage by influencing chromatin dynamics

Abstract

The interplay between circadian clocks, the cell cycle, and DNA repair has been extensively documented, yet the epigenetic control of circadian clocks by DNA damage responses remains relatively unexplored. Here, we showed that checkpoint kinases CHK1/2 regulate chromatin structure during DNA damage in Neurospora crassa to maintain robust circadian rhythms. Under DNA damage stress, deletion of chk1/2 disrupted the rhythmic transcription of the clock gene frq by suppressing the rhythmic binding of the transcription activator White Collar complex (WCC) at the frq promoter, as the chromatin structure remained condensed. Mechanistically, CHK1/2 interacted with WC-2 and were recruited by WCC to bind at the frq promoter to phosphorylate H3T11, promoting H3 acetylation, especially H3K56 acetylation, to counteract the histone variant H2A.Z deposition, thereby establishing a suitable chromatin state to maintain robust circadian rhythms despite DNA damage. Additionally, a genome-wide correlation was discovered between H3T11 phosphorylation and H3K56 acetylation, showing a specific function at the frq promoter that is dependent on CHK1/2. Furthermore, transcriptome analysis revealed that CHK1/2 are responsible for robust rhythmic transcription of metabolic and DNA repair genes during DNA damage. These findings highlight the essential role of checkpoint kinases in maintaining robust circadian rhythms under DNA damage stress.