ALBERT

Description: Publication date: Available online 3 October 2013 Source: Cell Reports Author(s): Hong Wu , Nikolas Mathioudakis , Boubou Diagouraga , Aiping Dong , Ludmila Dombrovski , Frédéric Baudat , Stephen Cusack , Bernard de Massy , Jan Kadlec PRDM9, a histone lysine methyltransferase, is a key determinant of the localization of meiotic recombination hot spots in humans and mice and the only vertebrate protein known to be involved in hybrid sterility. Here, we report the crystal structure of the PRDM9 methyltransferase domain in complex with a histone H3 peptide dimethylated on lysine 4 (H3K4me2) and S-adenosylhomocysteine (AdoHcy), which provides insights into the methyltransferase activity of PRDM proteins. We show that the genuine substrate of PRDM9 is histone H3 lysine 4 (H3K4) and that the enzyme possesses mono-, di-, and trimethylation activities. We also determined the crystal structure of PRDM9 in its autoinhibited state, which revealed a rearrangement of the substrate and cofactor binding sites by a concerted action of the pre-SET and post-SET domains, providing important insights into the regulatory mechanisms of histone lysine methyltransferase activity. Graphical abstract Teaser The histone methyltransferase PRDM9 is a key determinant of meiotic recombination hot spots in humans and mice and the only vertebrate protein known to be involved in hybrid sterility. In this study, de Massy, Kadlec, and colleagues analyzed PRDM9 substrate specificity and report the crystal structures of its methyltransferase domain in an autoinhibited state and in complex with an H3K4me2 peptide and AdoHcy. These data provide important insights into the regulatory mechanisms of histone lysine methyltransferase activity.