Dependency of Heterochromatin Domains on Replication Factors

Chromatin structure regulates both genome expression and dynamics in eukaryotes where large heterochromatic regions are epigenetically silenced through the methylation of histone H3K9, histone deacetylation, and assembly of repressive complexes. Previous genetic screens with the fission yeast Schizosaccharomyces pombe have led to the identification of key enzymatic activities and structural constituents of heterochromatin. We report here on additional factors discovered by screening a library of deletion mutants for silencing defects at the edge of a heterochromatic domain bound by its natural boundary - the IR-R⁺ element - or by ectopic boundaries. We found that several components of the DNA replication progression complex (RPC) including Mrc1/Claspin, Mcl1/Ctf4, Swi1/Timeless, Swi3/Tipin and the FACT subunit Pob3 are essential to robust heterochromatic silencing, as are the ubiquitin ligase components Pof3 and Def1 that have been implicated in the removal of stalled DNA and RNA polymerases from chromatin. Moreover, the search identified the cohesin release factor Wpl1 and the forkhead protein Fkh2, both likely to function through genome organization, as well as the Ssz1 chaperone, the Fkbp39 proline cis-trans isomerase, that acts on histone H3P30 and P38 in S. cerevisiae, and the chromatin remodeler Fft3. In addition to their effects in the mating-type region, these factors take part in heterochromatic silencing in pericentromeric regions and telomeres, to various extent, revealing for many a general effect in heterochromatin. This list of factors provides precious new clues with which to study the spatio-temporal organization and dynamics of heterochromatic regions in connection with DNA replication.

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