Compartmentalization of DNA Damage Response between Heterochromatin and Euchromatin Is Mediated by Distinct H2A Histone Variants

DNA double-strand break (DSB) repair depends on the ataxia telangiectasia mutated (ATM) kinase that phosphorylates the conserved C-terminal SQ motif present in the histone variant H2A.X [1–7]. In constitutive heterochromatin of mammals, DSB repair is delayed and relies on phosphorylation of the proteins HP1 and KAP1 by ATM [2, 8–14]. However, KAP1 is not conserved in plants and the HP1-related protein Like-HP1 (LHP1) is not localized at constitutive heterochromatin [15], suggesting that in plants, alternative mechanisms could be responsible for repair of DSBs in heterochromatin. In Arabidopsis, constitutive heterochromatin is marked by H3K9 methylation and the plant-specific histone variants H2A.W, which are distinguished by their C-terminal motif KSPKK and required for heterochromatin compaction [16–18]. We report that the Arabidopsis histone variant H2A.W.7 is confined to heterochromatin and carries a SQ motif that is phosphorylated by ATM. In response to DNA damage, phosphorylation of H2A.W.7 takes place in heterochromatin, while H2A.X phosphorylation takes place primarily in euchromatin. We propose that H2A.W.7 evolved in addition to H2A.X to facilitate DNA damage response in highly condensed heterochromatin, thus playing a role similar to KAP1 and HP1 phosphorylation in mammals. These data support the idea of the functional diversification of histone variants and their role in spatial compartmentalization of chromatin-related functions in eukaryotes.