Department of Biological Sciences, Lehigh University, Bethlehem, Pennsylvania, United States of America.
PLoS One. 2020 Dec 29;15(12):e0242968. doi: 10.1371/journal.pone.0242968. eCollection 2020.
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.
酵母 Eco1（人类中的 ESCO2）乙酰转移酶将染色质结合的黏连蛋白转化为 DNA 连接状态，从而建立姐妹染色单体的黏合。Eco1 在 DNA 复制期间建立黏合，之后 Eco1 被 SCF E3 泛素连接酶靶向降解。SCF E3 泛素连接酶以及促进 Eco1 泛素化和降解的连续磷酸化在整个 M 期仍然活跃。这样，Eco1 蛋白水平在 S 期较高，但在整个细胞周期中保持较低水平。然而，在 M 期受到 DNA 损伤时，Eco1 活性增加，为新的黏合建立波（称为损伤诱导黏合，或 DIC）提供了支持，这对于有效修复 DNA 至关重要。迄今为止，关于 Eco1 活性在 M 期因 DNA 损伤而增加的机制几乎没有证据。可能性包括，靶向 Eco1 降解的激酶或 E3 连接酶在 DNA 损伤时被抑制。相反，我们的结果表明，降解机制在整个 M 期仍然保持完全活跃，尽管存在 DNA 损伤。在通过测试替代模型来研究 Eco1 活性如何响应 DNA 损伤而增加的过程中，结果表明，DNA 损伤诱导 Eco1 的新转录，其速率超过 Eco1 周转率，从而快速积累 Eco1 蛋白。我们进一步表明，DNA 损伤诱导的 ECO1 转录部分受 Yap5（一种应激诱导的转录因子）调节。鉴于突变型 ESCO2（ECO1 的同源物）在人类出生缺陷中的作用，本研究强调了 ESCO2 突变和 ESCO2 调节缺陷可能通过何种复杂方式促进发育异常，并导致各种疾病，包括癌症。
