Heterochromatin suppresses gross chromosomal rearrangements at centromeres by repressing Tfs1/TFIIS-dependent transcription

Heterochromatin that is characterized by histone H3 lysine 9 (H3K9) methylation assembles on repetitive regions including centromeres. Although centromeric heterochromatin is important for faithful segregation of chromosomes, its role in maintaining centromere integrity remains elusive. Here, we found in fission yeast that heterochromatin suppresses gross chromosomal rearrangements (GCRs) at centromeres. Mutations in Clr4/Suv39 methyltransferase increased the formation of isochromosomes whose breakpoints are present in centromere repeats. H3K9A and H3K9R mutations also increased GCRs, suggesting that Clr4 appears to suppress GCRs via H3K9 methylation. Both HP1 homologs, Swi6 and Chp2, and an RNAi component Chp1 were the chromodomain proteins that are essential for full suppression of GCRs. Remarkably, mutations in RNA polymerase II (RNAPII) or the transcription factors including Tfs1/TFIIS which facilitates restart of backtracked RNAPII specifically bypassed the requirement of Clr4 to s...以组蛋白H3赖氨酸9（H3K9）甲基化为特征的异染色质（Heterochromatin），可在着丝粒等重复基因组区域组装。尽管着丝粒异染色质对于染色体的精准分离至关重要，但其在维持着丝粒完整性方面的具体作用仍有待阐明。本研究以裂殖酵母为研究对象，发现异染色质可抑制着丝粒区域发生的大规模染色体重排（gross chromosomal rearrangements, GCRs）。Clr4/Suv39甲基转移酶的编码基因突变，会显著增加以着丝粒重复序列为断裂位点的等臂染色体的形成频率。H3K9A与H3K9R突变同样会提升GCR的发生概率，这表明Clr4可能通过介导H3K9甲基化发挥GCR抑制作用。异染色质蛋白1（HP1）的同源蛋白Swi6与Chp2，以及RNA干扰（RNAi）通路组分Chp1均属于染色质域（chromodomain）蛋白，是完全抑制GCR发生所必需的因子。值得注意的是，RNA聚合酶II（RNA polymerase II, RNAPII）的突变，或是包括可促进回溯型RNA聚合酶II重启的Tfs1/TFIIS在内的转录因子发生突变，均可特异性地绕过Clr4对GCR的抑制需求……