Abstract
Yeast Eco1 (ESCO2 in humans) acetyltransferase converts chromatin-bound cohesins to a DNA tethering state, thereby establishing sister chromatid cohesion. Eco1 establishes cohesion during DNA replication, after which Eco1 is targeted for degradation by SCF E3 ubiquitin ligase. SCF E3 ligase, and sequential phosphorylations that promote Eco1 ubiquitination and degradation, remain active throughout the M phase. In this way, Eco1 protein levels are high during S phase, but remain low throughout the remaining cell cycle. In response to DNA damage during M phase, however, Eco1 activity increases-providing for a new wave of cohesion establishment (termed Damage-Induced Cohesion, or DIC) which is critical for efficient DNA repair. To date, little evidence exists as to the mechanism through which Eco1 activity increases during M phase in response to DNA damage. Possibilities include that either the kinases or E3 ligase, that target Eco1 for degradation, are inhibited in response to DNA damage. Our results reveal instead that the degradation machinery remains fully active during M phase, despite the presence of DNA damage. In testing alternate models through which Eco1 activity increases in response to DNA damage, the results reveal that DNA damage induces new transcription of ECO1 and at a rate that exceeds the rate of Eco1 turnover, providing for rapid accumulation of Eco1 protein. We further show that DNA damage induction of ECO1 transcription is in part regulated by Yap5-a stress-induced transcription factor. Given the role for mutated ESCO2 (homolog of ECO1) in human birth defects, this study highlights the complex nature through which mutation of ESCO2, and defects in ESCO2 regulation, may promote developmental abnormalities and contribute to various diseases including cancer.