SUV39 SET domains mediate crosstalk of heterochromatic histone marks

eLife

Alessandro Stirpe¹  Thomas Schalch²  Beat Fierz³  Nora Guidotti³  Sinan Kilic³  Sarah J Northall⁴  Oscar Vadas⁵  Alexandre Hainard⁶ 

[1] Department of Molecular Biology, Faculty of Science, University of Geneva, Geneva, Switzerland;Department of Molecular Biology, Faculty of Science, University of Geneva, Geneva, Switzerland;Leicester Institute for Structural and Chemical Biology, University of Leicester, Leicester, United Kingdom;Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom;Institute of Chemical Sciences and Engineering (ISIC), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland;Leicester Institute for Structural and Chemical Biology, University of Leicester, Leicester, United Kingdom;Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom;School of Pharmaceutical Sciences, Faculty of Science, University of Geneva, Geneva, Switzerland;University Medical Center, University of Geneva, Geneva, Switzerland;

关键词: heterochromatin;    methyltransferase;    ubiquitin;    posttranslational modifications;    enzyme kinetics;    protein complex;    S. pombe;   

DOI  :  10.7554/eLife.62682

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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 Schizosaccharomyces 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 remain 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 harbors a conserved sensor for H3K14ub, which mediates licensing of heterochromatin formation.

【 授权许可】

CC BY