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Symmetric control of sister chromatid cohesion establishment.

Nucleic acids research (2023-03-14)
Jiaxin Zhang, Lili Li, Yu Miao, Xiaojing Liu, Haitao Sun, Meiqian Jiang, Xiaoli Li, Zhen Li, Cong Liu, Baohua Liu, Xingzhi Xu, Qinhong Cao, Wenya Hou, Chunlai Chen, Huiqiang Lou
ABSTRACT

Besides entrapping sister chromatids, cohesin drives other high-order chromosomal structural dynamics like looping, compartmentalization and condensation. ESCO2 acetylates a subset of cohesin so that cohesion must be established and only be established between nascent sister chromatids. How this process is precisely achieved remains unknown. Here, we report that GSK3 family kinases provide higher hierarchical control through an ESCO2 regulator, CRL4MMS22L. GSK3s phosphorylate Thr105 in MMS22L, resulting in homo-dimerization of CRL4MMS22L and ESCO2 during S phase as evidenced by single-molecule spectroscopy and several biochemical approaches. A single phospho-mimicking mutation on MMS22L (T105D) is sufficient to mediate their dimerization and rescue the cohesion defects caused by GSK3 or MMS22L depletion, whereas non-phosphorylable T105A exerts dominant-negative effects even in wildtype cells. Through cell fractionation and time-course measurements, we show that GSK3s facilitate the timely chromatin association of MMS22L and ESCO2 and subsequently SMC3 acetylation. The necessity of ESCO2 dimerization implicates symmetric control of cohesion establishment in eukaryotes.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-acetyl SMC3 Antibody (Lys105/106), clone 21A7, clone 21A7, from mouse
Sigma-Aldrich
Monoclonal ANTI-FLAG® M2 antibody produced in mouse, clone M2, purified immunoglobulin (Purified IgG1 subclass), buffered aqueous solution (10 mM sodium phosphate, 150 mM NaCl, pH 7.4, containing 0.02% sodium azide)