Crosstalk between H2A variant-specific modifications impacts vital cell functions

Schmücker, Anna ; Lei, Bingkun ; Lorković, Zdravko J. ; Capella, Matías ; Braun, Sigurd ; Bourguet, Pierre ; Mathieu, Olivier ; Mechtler, Karl und Berger, Frédéric (2021): Crosstalk between H2A variant-specific modifications impacts vital cell functions.
In: PLOS Genetics 17(6), e1009601

Abstract

Selection of C-terminal motifs participated in evolution of distinct histone H2A variants. Hybrid types of variants combining motifs from distinct H2A classes are extremely rare. This suggests that the proximity between the motif cases interferes with their function. We studied this question in flowering plants that evolved sporadically a hybrid H2A variant combining the SQ motif of H2A.X that participates in the DNA damage response with the KSPK motif of H2A.W that stabilizes heterochromatin. Our inventory of PTMs of H2A.W variants showed that in vivo the cell cycle-dependent kinase CDKA phosphorylates the KSPK motif of H2A.W but only in absence of an SQ motif. Phosphomimicry of KSPK prevented DNA damage response by the SQ motif of the hybrid H2A.W/X variant. In a synthetic yeast expressing the hybrid H2A.W/X variant, phosphorylation of KSPK prevented binding of the BRCT-domain protein Mdb1 to phosphorylated SQ and impaired response to DNA damage. Our findings illustrate that PTMs mediate interference between the function of H2A variant specific C-terminal motifs. Such interference could explain the mutual exclusion of motifs that led to evolution of H2A variants. Author summary DNA is wrapped around nucleosomes constituted by histones. Variants of histones diversified during evolution. The evolutionary path that led to selection of C-terminal motifs specific of each class of H2A variant is largely unknown. Here we show that cell cycle dependent kinases phosphorylate the KSPK motif identifying the heterochromatin-associated variant H2A.W that evolved in vascular plants. In all eukaryotes, H2A.X carries the SQ motif that is phosphorylated in response to DNA damage. Assembling both motifs in the C-terminal tail is rarely seen in hybrid H2A.W/X variants that evolved in a few plant species. Genetic manipulations in Arabidopsis show that this is possible only if phosphorylation of the KSPK motif is prevented. A synthetic strategy using yeast shows that KSPK phosphorylation interferes with the recognition of the reader of phosphorylated SQ and hampers with DNA damage response. This study proposes that interference between the function carried by C-terminal motifs led to their mutual exclusion achieving evolution of distinct classes of H2A variants.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1553-7404
• Sprache: Englisch