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

Abstract

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.

Comprehensive Interactome Mapping of the DNA Repair Scaffold SLX4 using Proximity Labeling and Affinity Purification

“…The SLX4 interactome contains several high-confidence preys that function in chromosome structure and dynamics, most notably chromosome/chromatid cohesion. For example, we detected the vast majority of the subunits that form cohesin, a multiprotein complex containing two coiled-coil subunits, SMC1A and SMC3, the kleisin subunit RAD21, and the additional regulatory subunits SA1/2 and PDS5A/B [76, 77]. We also detected an interaction between SLX4 and NIPBL, which functions as the cohesin loading complex.…”

“…We also detected an interaction between SLX4 and NIPBL, which functions as the cohesin loading complex. The canonical role of cohesin is to ensure faithful chromosome segregation by holding sister chromatids together after DNA replication until the onset of anaphase in mitosis [76, 77]. However, cohesin also has an important role in DNA double-strand break repair, where it promotes accurate repair by HR using the sister chromatid as the template.…”

Senescence in yeast is associated with chromosome XII cleavage rather than ribosomal DNA circle accumulation

“…Alternatively, rDNA silencing by Sir2 affects rDNA recombination in young cells through cohesin displacement; cohesin is lost from the rDNA during ageing and cohesin anchoring mutants undergo accelerated loss of heterozygosity with reduced lifespan, suggesting that aged cells are more sensitive to cohesin impairment (Chan et al, 2011; Kobayashi and Ganley, 2005; Lindstrom et al, 2011; Pal et al, 2018). Cohesin displacement is thought to directly affect rDNA recombination reactions by increasing freedom of broken chromosome ends, but the effect may be less direct in ageing cells as cohesin is involved in replication fork restart (Kobayashi et al, 2004; Tittel-Elmer et al, 2012; van Schie and de Lange, 2021). In other words, cohesin displacement would also increase unrecoverable replication fork stalling, increasing the frequency at which cells enter anaphase with incompletely replicated rDNA (Figure 6A).…”

The multifaceted roles of cohesin in cancer

“…DNA replication fork progression can be challenged by several factors, such as presence of DNA lesions, inappropriate origin firing, the presence of unresolved DNA secondary structures, deficiency of nucleotide pools available for DNA synthesis, and presence of DNA–RNA hybrid intermediates, leading to transient replication fork progression defects. This replication stress can lead to stalling of DNA polymerases, and prolonged stalling can result in fork breakage due to fork collapse or nucleolytic processing of replication intermediates [ 148 , 149 ]. The presence of transcriptionally engaged Pol II without productive elongation (promoter-proximal paused Pol II) was first observed for the c- myc and c- fos genes in mammalian cells [ 150 , 151 ].…”