Physical basis for long-distance communication along meiotic chromosomes

Abstract

Viable gamete formation requires segregation of homologous chromosomes connected, in most species, by cross-overs. DNA double-strand break (DSB) formation and the resulting cross-overs are regulated at multiple levels to prevent overabundance along chromosomes. Meiotic cells coordinate these events between distant sites, but the physical basis of long-distance chromosomal communication has been unknown. We show that DSB hotspots up to ∼200 kb (∼35 cM) apart form clusters via hotspot-binding proteins Rec25 and Rec27 in fission yeast. Clustering coincides with hotspot competition and interference over similar distances. Without Tel1 (an ATM tumor-suppressor homolog), DSB and crossover interference become negative, reflecting coordinated action along a chromosome. These results indicate that DSB hotspots within a limited chromosomal region and bound by their protein determinants form a clustered structure that, via Tel1, allows only one DSB per region. Such a "roulette" process within clusters explains the observed pattern of crossover interference in fission yeast. Key structural and regulatory components of clusters are phylogenetically conserved, suggesting conservation of this vital regulation. Based on these observations, we propose a model and discuss variations in which clustering and competition between DSB sites leads to DSB interference and in turn produces crossover interference.

DNA-dependent macromolecular condensation drives self-assembly of the meiotic DNA break machinery

“…In this view, loops within a cluster compete with one another for access to the DSB machinery. Hotspot clustering has also been proposed as a means to control DSB patterning in S. pombe (Fowler et al, 2018). Once activated, the machinery has potential to make multiple cuts, but this is suppressed by Tel1 after the first DSB is made.…”

Dynamic configurations of meiotic hotspot determinants

“…Both DSB interference and crossover interference depend on the Tel1 DNA damage-response protein kinase, consistent with crossover interference resulting from DSB interference. The physical distance of 200 kb is about 35 cM in S. pombe (Fowler et al, 2018), which is similar to the extent, in genetic distance, of crossover interference in Drosophila melanogaster and Neurospora crassa (Foss et al, 1993). The clustering model predicts that LinE clusters regulate crossover interference within ~200 kb regions in S. pombe, as observed.…”

“…Several models of CO interference have been proposed, but the molecular basis of most of these models is not clear (King and Mortimer, 1990;Foss et al, 1993;Foss and Stahl, 1995;Fujitani et al, 2002;Kleckner et al, 2004;Hultén, 2011). Based on both genetic and molecular evidence, Fowler et al (2018) proposed a "clustering model" in which CO interference is the outcome of DSB interference, which has an identified molecular basis.…”

“…The clustering model proposes that DSB hotspots bound by LinEs along a limited chromosomal region form a compact, three-dimensional cluster before DSB formation, and a limited number of DSBs (perhaps only one) is formed per cluster (Fowler et al, 2018;Nambiar et al, 2019). With a modification of the genome-wide chromatin conformation capture (3C) technique (Dekker et al, 2002;Fowler et al, 2018), Fowler et al (2018 showed that the DSB-determining LinEs within a roughly 200 kb region form hotspot clusters. They showed that both DSB competition and DSB interference are also limited to ~200 kb regions.…”

Population genetics of the highly polymorphicRPP8gene family

“…However, we note that this model does not take into account known effects of chromosomal interference at distances shorter than 200 kb. Chromosomal interference is known to reduce crossovers and the number of double-strand breaks, thus also reducing the number of noncrossover events [79]. Regardless, the 2 Mb distance between the RPP8 paralogs is an order of magnitude greater than 200 kb.…”