An H3K79 Methylation-Dependent Checkpoint Blocks Holliday Junction Resolution and Meiotic Divisions under Heat Stress

Meiosis, the specialized cell division that produces haploid gametes from diploid precursors, is markedly more sensitive to heat stress than mitosis in a wide range of organisms, despite the two processes utilizing largely overlapping cellular machinery. The mechanistic basis of meiotic heat sensitivity has remained unclear. Here, we show that in budding yeast, even moderate heat stress impairs the processing of programmed double-strand breaks into crossovers, resulting in permanent meiotic division arrest. This arrest depends on methylation of histone H3 at lysine 79 (H3K79) by Dot1, and a subset of other components of the meiotic recombination checkpoint. Thus, in contrast to the canonical heat shock response that adapts mitotically dividing cells to elevated temperatures, meiotic arrest is triggered by stalled recombination intermediates in the context of the H3K79 chromatin modification. These findings suggest a conserved epigenetic pathway responsible for heat-induced meiotic failure across eukaryotes. Genetically enhancing the heat tolerance of meiotic chromosome metabolism may increase reproductive resilience of organisms facing rising global temperatures, bridging the gap until mitigation strategies are in place.

Meiosis generates haploid gametes through a specialized cell division that involves crossovers between homologous chromosomes. Crossovers promote genetic diversity and ensure proper chromosome segregation during meiosis I. In many organisms, meiosis stalls under moderate heat stress at temperatures permissive for mitosis, a phenomenon with implications for crop fertility and stability of ecosystems. Using yeast, we discovered that heat stress blocks meiosis at Holliday junctions - the four-armed DNA intermediates that resolve into crossovers - while alternative non-crossovers form normally. Arrest depends on the H3K79 methylation-dependent checkpoint involving Dot1. Thus, heat sensitivity of meiosis stems from checkpoint surveillance of impaired chromosome interactions. Modulating the underlying mechanism could enhance reproductive resilience to a warming climate.