Interference between DNA breaks during gamete formation

Meiotic recombination is a critical step in gametogenesis for many organisms, enabling the creation of genetically diverse haploid gametes. Regulating the distribution of recombination events so that they are evenly spread across all chromosomes is fundamental for both maintaining genome stability and promoting genetic variation. Here we demonstrate that meiotic DNA breaks (DSBs), the precursors of those recombination events, are not distributed randomly. Moreover, we demonstrate that the evolutionarily conserved tumour suppressor protein Tel1/ATM is necessary to promote this even distribution and—strikingly—to suppress clustering of DNA breaks within chromatin loops.

HFSP Career Development Award holder Matthew Neale and colleagues
authored on Mon, 16 February 2015

DSB interference: During gametogenesis, in each meiotic cell, recombination is initiated by numerous DNA breaks (DSBs) created by Spo11, an evolutionarily conserved topoisomerase-like protein. Whilst DNA breaks can be generated within most locations in the genome, the mechanisms that cause them to be relatively evenly distributed in any individual cell are poorly understood. In the recent study carried out by the Neale lab at the University of Sussex, we employed the unicellular sexually-reproducing eukaryote Saccharomyces cerevisiae (commonly referred to as “baker’s” or “budding” yeast) to demonstrate for the first time distance-dependent inhibition between DNA breaks: essentially the occurrence of one DNA break suppresses further DNA breaks from forming in the local chromosomal region. Collectively, when played out across the few hundred events spread across the genome, this process will help to “push” DNA breaks—and therefore sites of genetic recombination—further apart, thereby encouraging greater genetic variability within individual gametes, and by extension, within sexually reproducing populations. We term this process of regulation: “DSB interference”.

DSB Regulation by Tel1/ATM: The human tumour suppressor protein, ATM, is an evolutionarily conserved signalling kinase that responds to DNA damage, and is important in normal cellular growth to coordinate transient cell cycle regulation with DNA repair activity. Importantly, we found that DSB interference is mediated by Tel1 (the budding yeast equivalent of human ATM gene); presumably an evolutionarily conserved repurposing of the activity of these signalling kinases to influence not just the DNA repair and cell division process, but also the distribution of genetic change within gamete cells. Intriguingly, we found that the inhibitory function of Tel1 acts on a relatively local scale, while over large distances DSBs have a tendency to form independently of one another even in the presence of Tel1. Our findings suggest that the substrate(s) that Tel1 (and likely ATM) regulates are held and repressed locally within the chromosomal region surrounding a DNA break.

Clustering of DNA breaks:The meiotic chromosomes are organized into a linear array of DNA loops emanating from and assembled upon what is referred to as the “chromosome axis”. Remarkably, over relatively short distances (when DNA breaks are less than 10 thousand DNA basepairs apart [note the yeast genome is 12 million basepairs long, whereas that of humans is 3 billion basepairs long]), we discovered a very different impact of loss of Tel1: clustering of DNA breaks at frequencies greater than expected by random chance. Moreover, the genomic regions over which such clustered DNA break formation arose correlated well with the inferred position of individual chromosome loops. We propose that DNA break formation arises by activation—perhaps better referred to as “priming”—of an individual loop domain, such that the efficiency of Spo11 catalysis within such a region is greatly increased. We propose that under normal circumstances—following formation of the first DNA break—local Tel1/ATM-mediated inhibition would prevent additional DNA breaks forming in the same chromosome loop. By contrast, when Tel1/ATM activity is absent, clusters of DNA breaks arise within relatively short regions of the genome. The concept that meiotic DNA breaks might cluster is unprecedented, and will have a major impact on the way researchers consider and model rates and distributions of recombination occurring during gametogenesis.

Wider outlook:ATM and its related sister kinase ATR represent some of the most important enzymes involved in maintaining genome stability during human cell growth, chromosome replication and nuclear division. Mutation of either enzyme confers extreme sensitivity to chemicals or environmental agents that damage cellular DNA (such as oxidative stress from cell metabolism, or radiation exposure), and result in genetic disorders such as Ataxia Telangiectasia (from which the genes gain their acronym) and Seckel syndrome—which are characterized by severe defects in cognitive and immune system development, and growth retardation. Our identification of ATM as a regulator of the distribution of genetic variation during gametogenesis represents yet another important role for these multitasking master regulatory protein kinases, and helps to provide a molecular explanation for the previously characterized defects in fertility displayed by ATM-deficient individuals.


Tel1(ATM)-mediated interference suppresses clustered meiotic double-strand-break formation. Garcia V, Gray S, Allison RM, Cooper TJ, Neale MJ. Nature 2015, Jan 5. doi:10.1038/nature1399.

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