Cohesin dynamic association to chromatin and interfacing with replication forks in genome integrity maintenance

Abstract

Proliferating cells need to accurately duplicate and pass their genetic material on to daughter cells. Problems during replication and partition challenge the structural and numerical integrity of chromosomes. Diverse mechanisms, as the DNA replication checkpoint, survey the correct progression of replication and couple it with other cell cycle events to preserve genome integrity. The structural maintenance of chromosomes (SMC) cohesin complex primarily contributes to chromosome duplication by mediating the tethering of newly replicated sister chromatids, thus assisting their equal segregation in mitosis. In addition, cohesin exerts important functions in genome organization, gene expression and DNA repair. These are determined by cohesin's ability to bring together different DNA segments and, hence, by the fashion and dynamics of its interaction with chromatin. It recently emerged that cohesin contributes to the protection of stalled replication forks through a mechanism requiring its timely mobilization from unreplicated DNA and relocation to nascent strands. This mechanism relies on DNA replication checkpoint-dependent cohesin ubiquitylation and promotes nascent sister chromatid entrapment, likely contributing to preserve stalled replisome-fork architectural integrity. Here we review how cohesin dynamic association to chromatin is controlled through post-translational modifications to dictate its functions during chromosome duplication. We also discuss recent insights on the mechanism that mediates interfacing of replisome components with chromatin-bound cohesin and its contribution to the establishment of sister chromatid cohesion and the protection of stalled replication forks.

Cohesin occupancy and composition at enhancers and promoters are linked to DNA replication origin proximity inDrosophila

“…10B). This does not require that replisomes move through cohesin or new cohesin loading behind the fork as proposed in other models (Uhlmann 2016, Villa-Hernández andBermejo 2018). It is consistent with the finding that cohesin can remain chromosomebound and establish cohesion during DNA replication in the absence of the Wapl removal factor (Rhodes et al 2017).…”

“…Cohesin mediates sister chromatid cohesion to ensure accurate chromosome segregation and also plays roles in DNA repair and gene transcription (Dorsett and Ström 2012;Dorsett and Merkenschlager 2013;Uhlmann 2016, Morales andVilla-Hernández and Bermejo 2018). In Drosophila, cohesin facilitates enhancerpromoter communication and regulates activity of the Polycomb repressive complex 1 at silenced and active genes (Rollins et al 1999;Schaaf et al 2013a;Schaaf et al 2013b;Pherson et al 2017).…”

Replication Fork Barriers and Topological Barriers: Progression of DNA Replication Relies on DNA Topology Ahead of Forks

“…[ 28–32 ] Another set of newly developed methods, generally known as “genome wide” studies, allow identification of small variations in the genome itself or the association of specific proteins, such as polymerases and topoisomerases, to specific sites along the genome. [ 33–35 ] Although we recognize the value of the data obtained using all these different methods, here we restrict ourselves to discuss data obtained using 2D gels. For a detailed and excellent review of replication fork stalling at natural impediments see ref.…”

Replisome‐Cohesin Interfacing: A Molecular Perspective

“…Replisomes meet cohesin complexes previously loaded on chromatin as they progress throughout the genome in S‐phase. Cohesin has been reported to enrich at sites of DNA synthesis and cohesin and its regulators productively interact with replication machineries (these interactions were recently revised) . Even if cohesion establishment is tightly intertwined with replication progression, the molecular mechanisms through which cohesin interfaces with replisome components are not yet understood.…”

“…Cohesin has been reported to enrich at sites of DNA synthesis [11,99] and cohesin and its regulators productively interact with replication machineries (these interactions were recently revised). [100] Even if cohesion establishment is tightly intertwined with replication progression, the molecular mechanisms through which cohesin interfaces with replisome components are not yet understood. Several models for cohesin-fork interfacing have been considered (Figure 4).…”