SUV39 SET domains mediate crosstalk of heterochromatic histone marks

BioRxiv : the Preprint Server for Biology
A. StirpeS. Kilic

Abstract

The SUV39 class of methyltransferase enzymes deposits histone lysine 9 di- and tri-methylation (H3K9me2/3), the epigenetic hallmark of constitutive heterochromatin, which serves as the central recruitment platform for the heterochromatic silencing machinery. How these enzymes are regulated to mark specific genomic regions as heterochromatic is not well understood. Clr4 is the sole H3K9me2/3 methyltransferase in the fission yeast S.pombe and recent evidence suggests that ubiquitination of lysine 14 on H3 tail (H3K14) plays a key role in H3K9 methylation. However, the molecular mechanism of this regulation and its role in heterochromatin formation remains to be determined. Here we present a structure-function approach to understanding how the H3K14ub mark stimulates Clr4 activity in cis. These results show that the H3K14ub substrate binds specifically and tightly to the catalytic domain of Clr4, and thereby activates the enzyme by 250-fold. Mutations that disrupt this mechanism lead to a loss of H3K9me2/3 and abolish heterochromatin silencing similar to a clr4 deletion. Our work reveals a sensor for H3K14 ubiquitylation in the SET domain of Clr4, which mediates the licensing of heterochromatin formation by an epigenetic cross-tal...Continue Reading

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