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bioRxiv · 10.1101/2020.06.30.177071

SUV39 SET domains mediate crosstalk of heterochromatic histone marks

Stirpe, A.·Guidotti, N.·Northall, S.·Hainard, A.·Vadas, O.·Fierz, B.·Schalch, T.·Kilic, S.
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Abstract

The SUV39 class of methyltransferase enzymes deposits histone H3 lysine 9 di- and trimethylation (H3K9me2/3), the hallmark of constitutive heterochromatin. How these enzymes are regulated to mark specific genomic regions as heterochromatic is poorly understood. Clr4 is the sole H3K9me2/3 methyltransferase in the fission yeast S. pombe and recent evidence suggests that ubiquitination of lysine 14 on histone H3 (H3K14ub) plays a key role in H3K9 methylation. However, the molecular mechanism of this regulation and its role in heterochromatin formation remains to be determined. Our structure-function approach shows that the H3K14ub substrate binds specifically and tightly to the catalytic domain of Clr4, and thereby stimulates the enzyme by over 250-fold. Mutations that disrupt this mechanism lead to a loss of H3K9me2/3 and abolish heterochromatin silencing similar to clr4 deletion. Comparison with mammalian SET domain proteins suggests that the Clr4 SET domain harbours a conserved sensor for H3K14ub, which mediates licensing of heterochromatin formation.

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Stirpe, A., Guidotti, N., Northall, S., Hainard, A., Vadas, O., Fierz, B., Schalch, T., Kilic, S.. 2020-07-02. SUV39 SET domains mediate crosstalk of heterochromatic histone marks. https://doi.org/10.1101/2020.06.30.177071

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