At meiosis, recombination — or genetic crossing-over — is initiated by the formation of DNA double-strand breaks (DSBs). But, how breakage of the chromosomes is controlled has been a mystery. Even though the influence of chromatin has long been suspected, only recently have several studies, including one by Reddy and Villeneuve in Cell, indicated a possible role for histone modifications in DSB formation.

Reddy and Villeneuve identified the Caenorhabditis elegans him-17 gene in a genetic screen and found that him-17 mutants were defective in meiotic segregation of homologous chromosomes. The mutants also lacked chiasmata (the cytologically visible connections between homologous chromosomes that correspond to the position of the crossover), which reflects a failure to form crossovers. However, immunofluorescence studies showed that him-17 mutants did form normal pairs of homologous chromosomes, which were connected by a synaptonemal complex (the protein structure that holds the paired chromosomes together). So, the lack of crossover formation was not due to a defect in homologous pairing, or synapsis, but was probably caused by a defect in the recombination process itself.

An antibody against the DNA-strand-exchange protein RAD-51 — which associates with recombination intermediates — showed reduced staining in the nuclei of him-17 mutants compared with wild-type germlines. In addition, the induction of DSBs by γ-irradiation in him-17 mutants rescued the mutant phenotype, as efficient chiasmata formation occurred. This result was reminiscent of the rescue by artificially induced DSBs of the mutant phenotype of the topoisomerase-like protein SPO-11, which is necessary for initiating meiotic recombination through DSB formation. These and other data strongly imply that HIM-17 is required for DSB formation.

Using worms that carried a HIM-17 fluorescent fusion protein, the authors showed that HIM-17 localizes mainly to chromatin in germline nuclei during all meiotic stages up until diakinesis when the chromosomes are well separated. Given that HIM-17 seems to be associated with chromatin, Reddy and Villeneuve stained germlines with antibodies against specific histone modifications, and looked for differences between wild-type and him-17 mutant germlines. Interestingly, staining with an antibody against histone-H3 dimethyl-lysine 9 (H3MeK9) — a histone modification that is typical of compact, or 'closed', heterochromatin — showed reduced and/or delayed accumulation in the mutant.

The authors identified structural features that were shared between HIM-17 and three proteins that interact genetically with lin-35/Rb — which has been implicated in chromatin-modifying complexes. The loss of LIN-35/Rb enhanced the meiotic defects of him-17 partial loss-of-function mutants, which indicated that LIN-35/Rb itself can modulate DSB levels.

Reddy and Villeneuve propose that the HIM-17-dependent progressive compaction of the chromatin during meiotic prophase establishes “competence for DSB formation”. Several recent studies in yeast have also implicated histone modifications in DSB formation. However, whether there is a direct molecular link between histone modification and DSB formation remains to be established.