UCSF

The genetic material is packaged differentially at different phases of the cell cycle. In interphase, cells package their genome into heterochromatin and euchromatin domains, where genes are repressed or expressed based on cell identity. Heterochromatin, the gene-repressive structure, is regulated by different factors that control methylation and acetylation on histones. During cell division, these histone modifications are copied onto the newly synthesized DNA. The heterochromatin structure is seeded from nucleation DNA sequence that recruits other factors to spread the domain. In our studies, we found that the factors required for spreading heterochromatin in different genomic regions are highly variable. Notably, we proposed a mechanism by which Fkh2, a transcription factor, recruits Clr6 histone deacetylase complex I” to a nucleated heterochromatin domain that initiates the spread of heterochromatin domains. During mitosis, the chromatin is packaged into condensed chromosomes for faithful segregation of the duplicated genome. Progression through mitosis is regulated by the levels of a family of protein kinase complexes named Cyclin-Dependent Kinases (CDKs). The phosphorylation of numerous CDK substrates drives various mitosis events. We identified a novel phosphate-binding pocket on cyclins that aids in the timing of sequential multisite phosphorylation in CDK substrates and mitotic events. Loss of this pocket causes a mitotic delay in vivo as well as loss of multisite phosphorylation in various CDK substrates in vitro.