Crosstalk between H2A variant-specific modifications impacts vital cell functions

Author:

Schmücker AnnaORCID,Lei BingkunORCID,Lorković Zdravko J.ORCID,Capella MatíasORCID,Braun SigurdORCID,Bourguet PierreORCID,Mathieu OlivierORCID,Mechtler KarlORCID,Berger FrédéricORCID

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.

Funder

Gregor Mendel Institute

FWF

Deutsches Forschungszentrum für Gesundheit und Umwelt, Helmholtz Zentrum München

Horizon 2020 Framework Programme

Austrian Science Fund

Publisher

Public Library of Science (PLoS)

Subject

Cancer Research,Genetics (clinical),Genetics,Molecular Biology,Ecology, Evolution, Behavior and Systematics

Reference82 articles.

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