Patients with central serous chorioretinopathy have high circulating alpha-klotho concentrations.

Stress is a risk factor for central serous chorioretinopathy (CSC), but a suitable biomarker of this stress has not been identified. We aimed to evaluate alpha-klotho (αKl) as a potential biomarker of CSC. The circulating concentrations of αKl in patients diagnosed with acute or chronic CSC and treated at Hyogo College of Medicine between December 2019 and July 2021 were retrospectively compared with those of healthy individuals. We also compared the αKl concentrations of patients with acute or chronic CSC. Furthermore, we evaluated the relationships of age, sex, smoking status, and subfoveal choroidal thickness (SFCT) with αKl concentration. Patients in whom subretinal fluid reaccumulated in the same eye after its resolution were defined as having recurrent CSC. We studied 56 patients (46 men and 10 women) and 27 healthy controls (19 men and 8 women); and 38 and 18 eyes with acute and chronic CSC, respectively. The mean circulating concentration of αKl was higher in patients with CSC than in controls (827±232 and 724±183 pg/mL, respectively; p = 0.035). The mean SFCT was greater in patients with CSC than in controls (416±91.0 and 278±96.3 µm, respectively; p<0.0001). The mean αKl concentration was significantly higher in the patients with acute CSC than in those with chronic CSC (898±221 and 740±224 pg/mL, respectively; p = 0.038). Recurrence of CSC occurred in 10 of 56 (17.9%) eyes, of which five eyes were in the acute CSC group and five were in the chronic CSC group. Patients who experienced recurrence had significantly higher αKI concentrations than those who did not (p = 0.0219). There were no significant relationships of αKl concentration with age, sex, smoking history, or SFCT. In summary, the circulating αKI concentrations of patients with CSC are high, which suggests that αKI may be an indicator of stress in such patients.

Opening of cohesin's SMC ring is essential for timely DNA replication and DNA loop formation.

The ring-shaped cohesin complex topologically binds to DNA to establish sister chromatid cohesion. This topological binding creates a structural obstacle to genome-wide chromosomal events, such as replication. Here, we examine how conformational changes in cohesin circumvent being an obstacle in human cells. We show that ATP hydrolysis-driven head disengagement, leading to the structural maintenance of chromosome (SMC) ring opening, is essential for the progression of DNA replication. Closure of the SMC ring stalls replication in a checkpoint-independent manner. The SMC ring opening also facilitates sister chromatid resolution and chromosome segregation in mitosis. Single-molecule analyses reveal that forced closure of the SMC ring suppresses the translocation of cohesin on DNA as well as the formation of stable DNA loops. Our results suggest that the ATP hydrolysis-driven SMC ring opening makes topologically bound cohesin dynamic on DNA to achieve replication-dependent cohesion in the S phase and to resolve cohesion in mitosis. Thus, the SMC ring opening could be a fundamental mechanism to modulate both cohesion and higher-order genome structure.

Drosophila Dalmatian combines sororin and shugoshin roles in establishment and protection of cohesion.

Sister chromatid cohesion is crucial to ensure chromosome bi-orientation and equal chromosome segregation. Cohesin removal via mitotic kinases and Wapl has to be prevented in pericentromeric regions in order to protect cohesion until metaphase, but the mechanisms of mitotic cohesion protection remain elusive in Drosophila Here, we show that dalmatian (Dmt), an ortholog of the vertebrate cohesin-associated protein sororin, is required for protection of mitotic cohesion in flies. Dmt is essential for cohesion establishment during interphase and is enriched on pericentromeric heterochromatin. Dmt is recruited through direct association with heterochromatin protein-1 (HP1), and this interaction is required for cohesion. During mitosis, Dmt interdependently recruits protein phosphatase 2A (PP2A) to pericentromeric regions, and PP2A binding is required for Dmt to protect cohesion. Intriguingly, Dmt is sufficient to protect cohesion upon heterologous expression in human cells. Our findings of a hybrid system, in which Dmt exerts both sororin-like establishment functions and shugoshin-like heterochromatin-based protection roles, provide clues to the evolutionary modulation of eukaryotic cohesion regulation systems.

Cohesin acetylation and Wapl-Pds5 oppositely regulate translocation of cohesin along DNA.

Cohesin is a ring-shaped protein complex that plays a crucial role in sister chromatid cohesion and gene expression. The dynamic association of cohesin with chromatin is essential for these functions. However, the exact nature of cohesin dynamics, particularly cohesin translocation, remains unclear. We evaluated the dynamics of individual cohesin molecules on DNA and found that the cohesin core complex possesses an intrinsic ability to traverse DNA in an adenosine triphosphatase (ATPase)-dependent manner. Translocation ability is suppressed in the presence of Wapl-Pds5 and Sororin; this suppression is alleviated by the acetylation of cohesin and the action of mitotic kinases. In Xenopus laevis egg extracts, cohesin is translocated on unreplicated DNA in an ATPase- and Smc3 acetylation-dependent manner. Cohesin movement changes from bidirectional to unidirectional when cohesin faces DNA replication; otherwise, it is incorporated into replicating DNA without being translocated or is dissociated from replicating DNA This study provides insight into the nature of individual cohesin dynamics and the mechanisms by which cohesin achieves cohesion in different chromatin contexts.