Abstract
Cohesin acetyltransferases ESCO1 and ESCO2 play a vital role in establishing sister chromatid cohesion. How ESCO1 and ESCO2 are controlled in a DNA replication-coupled manner remains unclear in higher eukaryotes. Here we show a critical role of CUL4-RING ligases (CRL4s) in cohesion establishment via regulating ESCO2 in human cells. Depletion of CUL4A, CUL4B or DDB1 subunits substantially reduces the normal cohesion efficiency. We also show that MMS22L, a vertebrate ortholog of yeast Mms22, is one of DDB1 and CUL4-associated factors (DCAFs) involved in cohesion. Several lines of evidence show selective interaction of CRL4s with ESCO2 through LxG motif, which is lost in ESCO1. Depletion of either CRL4s or ESCO2 causes a defect in SMC3 acetylation, which can be rescued by HDAC8 inhibition. More importantly, both CRL4s and PCNA act as mediators for efficiently stabilizing ESCO2 on chromatin and catalyzing SMC3 acetylation. Taken together, we propose an evolutionarily conserved mechanism in which CRL4s and PCNA promote ESCO2-dependent establishment of sister chromatid cohesion.
Highlights
Faithful genetic inheritance requires precise chromatin replication and separation of sister chromatids into two daughter cells
ESCO1 and ESCO2 have been known to catalyze the acetylation of a cohesin subunit SMC3, which triggers the establishment of sister chromatid cohesion
We have shown that CUL4-DDB1 ubiquitin ligases (CRL4MMS22L), in collaboration with PCNA, promote this key reaction
Summary
Faithful genetic inheritance requires precise chromatin replication and separation of sister chromatids into two daughter cells. To ensure accurate chromosome segregation in eukaryotic cells, each pair of sister chromatids must be aligned properly and held together by a cohesin complex from S phase to anaphase [1,2,3,4,5,6]. As cells proceed into S phase, cohesin binds more tightly to hold sister chromatids together (i.e. cohesive status). This transition is called the establishment of sister chromatid cohesion [5, 12]. Eco, whose essential substrate is proved to be Smc3 [13], triggers the cohesion establishment during S phase through counteracting the opposing activity of Rad (WAPL in human) [16]
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