Centromere identity and its epigenetic maintenance require the incorporation of a histone H3 variant called CENP-A at centromeres. CENP-A mislocalization to ectopic sites may disrupt chromatin-based processes and chromosome segregation, so it is important to uncover the mechanisms by which this variant is exclusively localized to centromeres. Here, we identify a role for the conserved chromatin-modifying complex FACT (facilitates chromatin transcription/transactions) in preventing budding yeast CENP-A Cse4 mislocalization to euchromatin by mediating its proteolysis. The Spt16 subunit of the FACT complex binds to Psh1 (Pob3/Spt16/ histone), an E3 ubiquitin ligase that targets CENP-A Cse4 for degradation. The interaction between Psh1 and Spt16 is critical for both CENP-A Cse4 ubiquitylation and its exclusion from euchromatin. We found that Psh1 cannot efficiently ubiquitylate CENP-A Cse4 nucleosomes in vitro, suggesting that additional factors must facilitate CENP-A Cse4 removal from chromatin in vivo. Consistent with this, a Psh1 mutant that cannot associate with FACT has a reduced interaction with CENP-A Cse4 in vivo. Together, our data identify a previously unknown mechanism to maintain centromere identity and genomic stability through the FACT-mediated degradation of ectopically localized CENP-A Cse4 .
The master regulators of the cell cycle are cyclin-dependent kinases (Cdks), which influence the function of a myriad of proteins via phosphorylation. Mitotic Cdk1 is activated by A-type, as well as B1- and B2-type, cyclins. However, the role of a third, conserved cyclin B family member, cyclin B3, is less well defined. Here, we show that Caenorhabditis elegans CYB-3 has essential and distinct functions from cyclin B1 and B2 in the early embryo. CYB-3 is required for the timely execution of a number of cell cycle events including completion of the MII meiotic division of the oocyte nucleus, pronuclear migration, centrosome maturation, mitotic chromosome condensation and congression, and, most strikingly, progression through the metaphase-to-anaphase transition. Our experiments reveal that the extended metaphase delay in CYB-3–depleted embryos is dependent on an intact spindle assembly checkpoint (SAC) and results in salient defects in the architecture of holocentric metaphase chromosomes. Furthermore, genetically increasing or decreasing dynein activity results in the respective suppression or enhancement of CYB-3–dependent defects in cell cycle progression. Altogether, these data reveal that CYB-3 plays a unique, essential role in the cell cycle including promoting mitotic dynein functionality and alleviation of a SAC–dependent block in anaphase chromosome segregation.
Lung cancer remains the world's deadliest cancer despite efforts to decrease smoking rates. Lung cancer screening (LCS) with low-dose computed tomography (LDCT) was shown to reduce lung cancer deaths by 20%. Screening with LDCT comes with potential harms including a high rate of false-positive test results, subsequent follow-up procedures, and radiation exposure. For some patients, the potential benefits associated with screening may be outweighed by the harms. The decision to screen must therefore take into consideration patients' risk of developing lung cancer, comorbidities that may prevent diagnostic procedures or curative surgery, and their values and preferences regarding the benefits and harms of screening. A process called shared decision-making (SDM) is recognized as a crucial feature of LCS. SDM is a patient-centered approach where healthcare providers provide best clinical evidence and then work together with patients to discern if the screening process aligns with the patient's values and preferences. Unfortunately, clinician SDM skills are often of poor quality which can lead to patients making uninformed decisions. Decision support tools that help patients make informed decisions and increase SDM on LCS are available. In 2015, the Centers for Medicare & Medicaid Services issued a coverage memo for LCS that contained an unprecedented requirement: an initial patient counseling and SDM visit with the use of at least one decision aid must occur for screening services to be reimbursed. This review focuses on SDM and suggests ways to increase the prevalence and effectiveness of SDM in LCS programs. Stopping smoking greatly reduces a person's risk for developing lung cancer, and smoking cessation messages in LCS guidelines from major medical organizations and interventions in LCS programs are explored. LCS has come of age; so too has SDM as it is an integral part of LCS programs.
The incorporation of histone variants into nucleosomes can alter chromatin-based processes. CENP-A is the histone H3 variant found exclusively at centromeres that serves as an epigenetic mark for centromere identity and is required for kinetochore assembly. CENP-A mislocalization to ectopic sites appears to contribute to genomic instability, transcriptional misregulation, and tumorigenesis, so mechanisms exist to ensure its exclusive localization to centromeres. One conserved process is proteolysis, which is mediated by the Psh1 E3 ubiquitin ligase in Saccharomyces cerevisiae (budding yeast). To determine whether there are features of the CENP-A nucleosome that facilitate proteolysis, we performed a genetic screen to identify histone H4 residues that regulate CENP-A degradation. We found that H4-R36 is a key residue that promotes the interaction between CENP-A and Psh1 Consistent with this, CENP-A protein levels are stabilized in H4-R36A mutant cells and CENP-A is enriched in the euchromatin. We propose that the defects in CENP-A proteolysis may be related to changes in Psh1 localization, as Psh1 becomes enriched at some 3' intergenic regions in H4-R36A mutant cells. Together, these data reveal a key residue in histone H4 that is important for efficient CENP-A degradation, likely by facilitating the interaction between Psh1 and CENP-A.
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