Scientists, like policemen, often have to work backwards — start with the motive to track down the culprit. Reporting in Nature, Downs et al. describe an example of such molecular detective work. They have linked phosphorylation of the Ser–Gln–Glu (SQE) motif in the yeast core histone H2A to alterations in chromatin — alterations that might facilitate the repair of damaged DNA.

The SQE motif is phosphorylated in vitro by members of the phosphatidylinositol-3-OH kinase-related kinase (PIKK) family. These include human ATM and ATR, and their Saccharomyces cerevisiae homologues Mec1p and Tel1p, all of which are central in eukaryotic responses to DNA damage.

Because the carboxyl terminus of histone H2A contains an SQE motif, Downs et al. wondered whether phosphorylation of this sequence might be involved in signalling DNA damage. They generated a strain in which the SQE motif was deleted, and found that it was hypersensitive to chemicals that induce DNA damage, such as methyl methane-sulphonate (MMS). When S, Q and E were mutated individually, the phenotypes correlated with the relative importance of each residue in defining an optimal PIKK-recognition motif. So could the hypersensitivity to MMS reflect loss of recognition by a PIKK? And if so, which one?

Strains with mutations in the MEC1 gene could not phosphorylate the SQE motif of H2A in the presence of MMS, indicating that H2A might be a direct target for Mec1p. Moreover, although phosphorylation of the SQE motif had no effect on Mec1p-dependent transcriptional or cell-cycle responses to DNA damage, it did seem to be necessary for Mec1p-dependent repair of double-stranded DNA breaks.

Given that H2A is a histone protein, one way of facilitating repair would be to alter the structure of chromatin around the broken DNA. This would allow the repair machinery easy access to the lesion. Consistent with this idea, Downs et al. found that in a mutant strain that mimicked the effect of phosphorylated SQE, the regions between individual nucleosomes were more sensitive to digestion by micrococcal nuclease — that is, compaction of the chromatin had been decreased.

The carboxyl terminus of H2A sits at the part of the nucleosome where DNA enters and exits, so it's ideally placed to influence the higher order structure of chromatin. How phosphorylation of the H2A carboxyl terminus leads to this effect is just one of the next lines of enquiry that the authors will be following up.