Biology subjects

Guacci, V.

Publications and source records attributed to Guacci, V..

3 recordsLinked to original sources

bioRxiv2026

Cohesin promotes genomic stability by suppressing unequal sister chromatid exchange

The protein complex cohesin plays critical roles in genomic stability by tethering together sister chromatids at their pericentric regions and along their arms from S phase until anaphase. Cohesin-mediated pericentric cohesion prevents aneuploidy by ensuring bipolar attachment of sister kinetochores. Arm cohesion prevents loss of heterozygosity by biasing DNA repair via recombination between sister chromatids rather than between homologs. Here, we investigate in yeast whether cohesin also enhances genomic stability by suppressing unequal sister chromatid exchange (USCE) between repetitive sequences. In wild-type cells, the USCE rate between repeats 4kb apart (proximal) was 15X higher than repeats 68kb apart (distal). The USCE between distal repeats but not proximal repeats increased 4 to 7-fold in mutants with altered cohesin subunits or auxiliary factors. The level of increased distal USCE corresponded with reduced arm cohesion, reduced density of cohesion arm sites, and higher sister loci mobility. Our results suggest that high density of arm cohesion sites confines repair of DNA damage to local sequences. When the density of cohesion sites decreases, sister chromatid sequences are less confined, thereby enhancing distal repeat interactions and USCE. Another set of mutations disrupted both DNA replication and cohesin loading at the replication fork during S phase. Remarkably, distal USCE in these mutants increased approximately 100-fold and was 6-fold more likely than proximal USCE. This preferential hyperdistal USCE can be explained by an aberrant sister-chromatid structure that is normally prevented by proper coupling of cohesin function and replication.

genetics↗

bioRxiv2017

A role for the Smc3 hinge domain in the maintenance of sister chromatid cohesion

Cohesin is a conserved protein complex required for sister chromatid cohesion, chromosome condensation, DNA damage repair, and regulation of transcription. Although cohesin functions to tether DNA duplexes, the contribution of its individual domains to this activity remains poorly understood. We interrogated the Smc3p subunit of cohesin by random insertion mutagenesis. Analysis of a mutant in the Smc3p hinge revealed an unexpected role for this domain in cohesion maintenance and condensation. Further investigation revealed that the Smc3p hinge functions at a step following cohesins stable binding to chromosomes and independently of Smc3ps regulation by the Eco1p acetyltransferase. Hinge mutant phenotypes resemble loss of Pds5p, which binds opposite the hinge near Smc3ps head domain. We propose that a specific conformation of the Smc3p hinge and Pds5p cooperate to promote cohesion maintenance and condensation.

cell biology↗

bioRxiv2017

Budding yeast Wpl1p regulates cohesin functions in cohesion, condensation and DNA repair by a common mechanism

Cohesin tethers DNA to mediate sister chromatid cohesion, chromosome condensation, and DNA repair. How the cell regulates cohesin to perform these distinct functions remains to be elucidated. One cohesin regulator, Wpl1p, was characterized in the budding yeast, Saccharomyces cerevisiae, as a promoter of cohesion and as an inhibitor of condensation. Here we provide evidence that Wpl1p has an additional function in promoting the timely repair of DNA damage induced during S-phase. In addition to these biological functions, Wpl1p has been implicated as an inhibitor of cohesins ability to stably bind DNA by modulating the interface between two subunits (Mcd1p and Smc3p) of the core cohesin complex. We show that Wpl1p likely modulates this interface to regulate all cohesins biological functions. Furthermore, we show that Wpl1p regulates cohesion and condensation through the formation of a functional complex with another cohesin-associated factor, Pds5p. In contrast, Wpl1p regulates DNA repair independently of its interaction with Pds5p. Together these results suggest that Wpl1p regulates distinct biological functions of cohesin by Pds5p-dependent and - independent modulation of the Smc3p-Mcd1p interface.

genetics↗