Cul4-Ddb1 ubiquitin ligases facilitate DNA replication-coupled sister chromatid cohesion through regulation of cohesin acetyltransferase Esco2

AbstractCohesin acetyltransferases Esco1 and Esco2 play a vital role in establishing sister chromatid cohesion. How Esco1 and Esco2 are controlled to achieve this in a DNA replication-coupled manner remains unclear in higher eukaryotes. Here we show that Cul4-RING ligases (CRL4s) play a critical role in sister chromatid cohesion in human cells. Depletion of Cul4A, Cul4B or Ddb1 subunits substantially reduces 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 suggest a selective interaction of CRL4s with Esco2, but not 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 regulate Esco2-dependent establishment of sister chromatid cohesion.Author summaryWe identified human Mms22L as a substrate specific adaptor of Cul4-Ddb1 E3 ubiquitin ligase. Downregulation of Cul4A, Cul4B or Ddb1 subunit causes reduction of acetylated Smc3, via interaction with Esco2 acetyltransferase, and then impairs sister chromatid cohesion in 293T cells. We found functional complementation between Cul4-Ddb1-Mms22L E3 ligase and Esco2 in Smc3 acetylation and sister chromatid cohesion. Interestingly, both Cul4-Ddb1 E3 ubiquitin ligase and PCNA contribute to Esco2 mediated Smc3 acetylation. To summarise, we demonstrated an evolutionarily conserved mechanism in which Cul4-Ddb1 E3 ubiquitin ligases and PCNA regulate Esco2-dependent establishment of sister chromatid cohesion.

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Decision letter: E3 ubiquitin ligase Bre1 couples sister chromatid cohesion establishment to DNA replication in Saccharomyces cerevisiae

10.7554/elife.28231.019 ◽

2017 ◽

Keyword(s):

Saccharomyces Cerevisiae ◽

Dna Replication ◽

Ubiquitin Ligase ◽

Sister Chromatid ◽

E3 Ubiquitin Ligase ◽

Sister Chromatid Cohesion ◽

Chromatid Cohesion

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Author response: E3 ubiquitin ligase Bre1 couples sister chromatid cohesion establishment to DNA replication in Saccharomyces cerevisiae

10.7554/elife.28231.020 ◽

2017 ◽

Author(s):

Wei Zhang ◽

Clarence Hue Lok Yeung ◽

Liwen Wu ◽

Karen Wing Yee Yuen

Keyword(s):

Saccharomyces Cerevisiae ◽

Dna Replication ◽

Ubiquitin Ligase ◽

Sister Chromatid ◽

E3 Ubiquitin Ligase ◽

Sister Chromatid Cohesion ◽

Author Response ◽

Chromatid Cohesion

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E3 ubiquitin ligase Bre1 couples sister chromatid cohesion establishment to DNA replication in Saccharomyces cerevisiae

eLife ◽

10.7554/elife.28231 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 9

Author(s):

Wei Zhang ◽

Clarence Hue Lok Yeung ◽

Liwen Wu ◽

Karen Wing Yee Yuen

Keyword(s):

Saccharomyces Cerevisiae ◽

Dna Replication ◽

Ubiquitin Ligase ◽

Sister Chromatid ◽

Structural Integrity ◽

Chromosome Instability ◽

E3 Ubiquitin Ligase ◽

Sister Chromatid Cohesion ◽

Chromatid Cohesion ◽

Early Replication

Bre1, a conserved E3 ubiquitin ligase in Saccharomyces cerevisiae, together with its interacting partner Lge1, are responsible for histone H2B monoubiquitination, which regulates transcription, DNA replication, and DNA damage response and repair, ensuring the structural integrity of the genome. Deletion of BRE1 or LGE1 also results in whole chromosome instability. We discovered a novel role for Bre1, Lge1 and H2Bub1 in chromosome segregation and sister chromatid cohesion. Bre1’s function in G1 and S phases contributes to cohesion establishment, but it is not required for cohesion maintenance in G2 phase. Bre1 is dispensable for the loading of cohesin complex to chromatin in G1, but regulates the localization of replication factor Mcm10 and cohesion establishment factors Ctf4, Ctf18 and Eco1 to early replication origins in G1 and S phases, and promotes cohesin subunit Smc3 acetylation for cohesion stabilization. H2Bub1 epigenetically marks the origins, potentially signaling the coupling of DNA replication and cohesion establishment.

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Functional Coupling between DNA Replication and Sister Chromatid Cohesion Establishment

International Journal of Molecular Sciences ◽

10.3390/ijms22062810 ◽

2021 ◽

Vol 22 (6) ◽

pp. 2810

Author(s):

Ana Boavida ◽

Diana Santos ◽

Mohammad Mahtab ◽

Francesca M. Pisani

Keyword(s):

Dna Replication ◽

Sister Chromatid ◽

Molecular Mechanisms ◽

Sister Chromatid Cohesion ◽

Functional Coupling ◽

Functional Link ◽

Chromatid Cohesion ◽

Evolutionarily Conserved ◽

Eukaryotic Organisms ◽

Replication Factors

Several lines of evidence suggest the existence in the eukaryotic cells of a tight, yet largely unexplored, connection between DNA replication and sister chromatid cohesion. Tethering of newly duplicated chromatids is mediated by cohesin, an evolutionarily conserved hetero-tetrameric protein complex that has a ring-like structure and is believed to encircle DNA. Cohesin is loaded onto chromatin in telophase/G1 and converted into a cohesive state during the subsequent S phase, a process known as cohesion establishment. Many studies have revealed that down-regulation of a number of DNA replication factors gives rise to chromosomal cohesion defects, suggesting that they play critical roles in cohesion establishment. Conversely, loss of cohesin subunits (and/or regulators) has been found to alter DNA replication fork dynamics. A critical step of the cohesion establishment process consists in cohesin acetylation, a modification accomplished by dedicated acetyltransferases that operate at the replication forks. Defects in cohesion establishment give rise to chromosome mis-segregation and aneuploidy, phenotypes frequently observed in pre-cancerous and cancerous cells. Herein, we will review our present knowledge of the molecular mechanisms underlying the functional link between DNA replication and cohesion establishment, a phenomenon that is unique to the eukaryotic organisms.

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Tex19.1 Regulates Acetylated SMC3 Cohesin and Prevents Aneuploidy in Mouse Oocytes

10.1101/102285 ◽

2017 ◽

Cited By ~ 2

Author(s):

Judith Reichmann ◽

Karen Dobie ◽

Lisa M. Lister ◽

Diana Best ◽

James H. Crichton ◽

...

Keyword(s):

Down Syndrome ◽

Ubiquitin Ligase ◽

Sister Chromatid ◽

Meiotic Chromosome ◽

E3 Ubiquitin Ligase ◽

Sister Chromatid Cohesion ◽

Mouse Oocytes ◽

Chromatid Cohesion ◽

Age Dependent ◽

Female Germline

AbstractAge-dependent oocyte aneuploidy, a major cause of Down syndrome, is associated with declining sister chromatid cohesion in postnatal oocytes. Here we show that cohesion in postnatal mouse oocytes is regulated by Tex19.1. We show that Tex19.1-/- oocytes have defects in the maintenance of chiasmata, mis-segregate their chromosomes during meiosis, and transmit aneuploidies to the next generation. By reconstituting aspects of this pathway in mitotic somatic cells, we show that Tex19.1 regulates an acetylated SMC3-marked subpopulation of cohesin by inhibiting the activity of the E3 ubiquitin ligase UBR2 towards specific substrates, and that UBR2 itself has a previously undescribed role in negatively regulating acetylated SMC3. Lastly, we show that acetylated SMC3 is associated with meiotic chromosome axes in oocytes, but that this is reduced in the absence of Tex19.1. These findings indicate that Tex19.1 maintains acetylated SMC3 and sister chromatid cohesion in postnatal oocytes, and prevents aneuploidy in the female germline.

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