Monoubiquitination of histone H2B by E3 ubiquitin ligase Bre1 is crucial for sister chromatid cohesion

Abstract

The cohesin complex tethers the sister chromatids together from S phase to anaphase, ensuring faithful chromosome segregation. Defects in cohesion result in premature sister chromatid separation and chromosome loss, which may lead to aneuploidy and chromosome instability (CIN), as commonly seen in solid tumors. In Sacchromyces cerevisiae, null mutant of Bre1, a conserved RING domain-containing E3 ubiquitin ligase responsible for histone H2B monoubiquitination (H2Bub), shows CIN. Bre1 is important for replication fork progression, nucleosome assembly, histone crosstalk, transcription elongation, DNA damage checkpoint and double strand break (DSB) repair. Here, we discovered that Bre1 and H2Bub are required for sister chromatid cohesion. We found that Bre1’s function in G1 and S phases contributes to sister chromatid cohesion establishment, but Bre1 does not affect cohesion loading in G1. We discovered that Bre1 play a role in recruiting cohesion establishment factors, Ctf4 and Ctf18, to chromatin, specifically at early replication origins in S cells. The result suggests that Bre1-mediated H2Bub may modulate the chromatin environment before S phase to facilitate the recruitment of cohesion establishment factors to the chromatin, so that cohesion can be established at the replication forks. Our study reveals a novel function of Bre1-mediated H2Bub in maintaining the chromosome stability.