Functional Coupling between DNA Replication and Sister Chromatid Cohesion Establishment

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

10.1101/414888 ◽

2018 ◽

Cited By ~ 1

Author(s):

Haitao Sun ◽

Jiaxin Zhang ◽

Jingjing Zhang ◽

Zhen Li ◽

Qinhong Cao ◽

...

Keyword(s):

Dna Replication ◽

Ubiquitin Ligase ◽

Sister Chromatid ◽

Critical Role ◽

E3 Ubiquitin Ligase ◽

Ubiquitin Ligases ◽

Sister Chromatid Cohesion ◽

Vital Role ◽

Chromatid Cohesion ◽

Evolutionarily Conserved

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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The Interplay of Cohesin and the Replisome at Processive and Stressed DNA Replication Forks

Cells ◽

10.3390/cells10123455 ◽

2021 ◽

Vol 10 (12) ◽

pp. 3455

Author(s):

Janne J.M. van Schie ◽

Job de Lange

Keyword(s):

Dna Replication ◽

Sister Chromatid ◽

Molecular Mechanisms ◽

Replication Stress ◽

Sister Chromatid Cohesion ◽

Key Factors ◽

Sister Chromatids ◽

Chromatid Cohesion ◽

Dna Replication Stress ◽

Subsequent Stabilization

The cohesin complex facilitates faithful chromosome segregation by pairing the sister chromatids after DNA replication until mitosis. In addition, cohesin contributes to proficient and error-free DNA replication. Replisome progression and establishment of sister chromatid cohesion are intimately intertwined processes. Here, we review how the key factors in DNA replication and cohesion establishment cooperate in unperturbed conditions and during DNA replication stress. We discuss the detailed molecular mechanisms of cohesin recruitment and the entrapment of replicated sister chromatids at the replisome, the subsequent stabilization of sister chromatid cohesion via SMC3 acetylation, as well as the role and regulation of cohesin in the response to DNA replication stress.

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Division of Labor between PCNA Loaders in DNA Replication and Sister Chromatid Cohesion Establishment

Molecular Cell ◽

10.1016/j.molcel.2020.03.017 ◽

2020 ◽

Vol 78 (4) ◽

pp. 725-738.e4

Author(s):

Hon Wing Liu ◽

Céline Bouchoux ◽

Mélanie Panarotto ◽

Yasutaka Kakui ◽

Harshil Patel ◽

...

Keyword(s):

Dna Replication ◽

Division Of Labor ◽

Sister Chromatid ◽

Sister Chromatid Cohesion ◽

Chromatid Cohesion

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Ctf4 Links DNA Replication with Sister Chromatid Cohesion Establishment by Recruiting the Chl1 Helicase to the Replisome

Molecular Cell ◽

10.1016/j.molcel.2016.05.036 ◽

2016 ◽

Vol 63 (3) ◽

pp. 371-384 ◽

Cited By ~ 65

Author(s):

Catarina P. Samora ◽

Julie Saksouk ◽

Panchali Goswami ◽

Ben O. Wade ◽

Martin R. Singleton ◽

...

Keyword(s):

Dna Replication ◽

Sister Chromatid ◽

Sister Chromatid Cohesion ◽

Chromatid Cohesion

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Ctf7p is essential for sister chromatid cohesion and links mitotic chromosome structure to the DNA replication machinery

Genes & Development ◽

10.1101/gad.13.3.307 ◽

1999 ◽

Vol 13 (3) ◽

pp. 307-319 ◽

Cited By ~ 311

Author(s):

R. V. Skibbens ◽

L. B. Corson ◽

D. Koshland ◽

P. Hieter

Keyword(s):

Dna Replication ◽

Sister Chromatid ◽

Mitotic Chromosome ◽

Chromosome Structure ◽

Sister Chromatid Cohesion ◽

Replication Machinery ◽

Chromatid Cohesion

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Towards a Structural Mechanism for Sister Chromatid Cohesion Establishment at the Eukaryotic Replication Fork

Biology ◽

10.3390/biology10060466 ◽

2021 ◽

Vol 10 (6) ◽

pp. 466

Author(s):

Sarah S. Henrikus ◽

Alessandro Costa

Keyword(s):

Single Molecule ◽

Sister Chromatid ◽

Replication Fork ◽

Genetic Material ◽

Sister Chromatid Cohesion ◽

Duplex Dna ◽

Structural Mechanism ◽

Chromatin Dynamics ◽

Chromatid Cohesion ◽

Replication Factors

Cohesion between replicated chromosomes is essential for chromatin dynamics and equal segregation of duplicated genetic material. In the G1 phase, the ring-shaped cohesin complex is loaded onto duplex DNA, enriching at replication start sites, or “origins”. During the same phase of the cell cycle, and also at the origin sites, two MCM helicases are loaded as symmetric double hexamers around duplex DNA. During the S phase, and through the action of replication factors, cohesin switches from encircling one parental duplex DNA to topologically enclosing the two duplicated DNA filaments, which are known as sister chromatids. Despite its vital importance, the structural mechanism leading to sister chromatid cohesion establishment at the replication fork is mostly elusive. Here we review the current understanding of the molecular interactions between the replication machinery and cohesin, which support sister chromatid cohesion establishment and cohesin function. In particular, we discuss how cryo-EM is shedding light on the mechanisms of DNA replication and cohesin loading processes. We further expound how frontier cryo-EM approaches, combined with biochemistry and single-molecule fluorescence assays, can lead to understanding the molecular basis of sister chromatid cohesion establishment at the replication fork.

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Replication Protein A-Directed Unloading of PCNA by the Ctf18 Cohesion Establishment Complex

Molecular and Cellular Biology ◽

10.1128/mcb.25.13.5445-5455.2005 ◽

2005 ◽

Vol 25 (13) ◽

pp. 5445-5455 ◽

Cited By ~ 85

Author(s):

Göran O. Bylund ◽

Peter M. J. Burgers

Keyword(s):

Dna Replication ◽

Dna Binding ◽

Sister Chromatid ◽

Protein A ◽

Replication Protein A ◽

Dna Binding Protein ◽

Sister Chromatid Cohesion ◽

Replication Protein ◽

Single Stranded Dna ◽

Chromatid Cohesion

ABSTRACT The replication clamp PCNA is loaded around DNA by replication factor C (RFC) and functions in DNA replication and repair. Regulated unloading of PCNA during the progression and termination of DNA replication may require additional factors. Here we show that a Saccharomyces cerevisiae complex required for the establishment of sister chromatid cohesion functions as an efficient unloader of PCNA. Unloading requires ATP hydrolysis. This seven-subunit Ctf18-RFC complex consists of the four small subunits of RFC, together with Ctf18, Dcc1, and Ctf8. Ctf18-RFC was also a weak loader of PCNA onto naked template-primer DNA. However, when the single-stranded DNA template was coated by the yeast single-stranded DNA binding protein replication protein A (RPA) but not by a mutant form of RPA or a heterologous single-stranded DNA binding protein, both binding of Ctf18-RFC to substrate DNA and loading of PCNA were strongly inhibited, and unloading predominated. Neither yeast RFC itself nor two other related clamp loaders, containing either Rad24 or Elg1, catalyzed significant unloading of PCNA. The Dcc1 and Ctf8 subunits of Ctf18-RFC, while required for establishing sister chromatid cohesion in vivo, did not function specifically in PCNA unloading in vitro, thereby separating the functionality of the Ctf18-RFC complex into two distinct paths.

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