title: Tel1(ATM)-mediated interference suppresses clustered meiotic double-strand-break formation.
abstract: Meiotic recombination is a critical step in gametogenesis for many organisms, enabling the creation of genetically diverse haploid gametes. In each meiotic cell, recombination is initiated by numerous DNA double-strand breaks (DSBs) created by Spo11, the evolutionarily conserved topoisomerase-like protein, but how these DSBs are distributed relatively uniformly across the four chromatids that make up each chromosome pair is poorly understood. Here we employ Saccharomyces cerevisiae to demonstrate distance-dependent DSB interference in cis (in which the occurrence of a DSB suppresses adjacent DSB formation)--a process that is mediated by the conserved DNA damage response kinase, Tel1(ATM). 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. Notably, over very short distances, loss of Tel1 activity causes DSBs to cluster within discrete zones of concerted DSB activity. Our observations support a hierarchical view of recombination initiation where Tel1(ATM) prevents clusters of DSBs, and further suppresses DSBs within the surrounding chromosomal region. Such collective negative regulation will help to ensure that recombination events are dispersed evenly and arranged optimally for genetic exchange and efficient chromosome segregation.
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK.
authors.forename: Valerie
authors.initials: V
authors.lastname: Garcia
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Gray
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK.
authors.forename: Rachal M
authors.initials: RM
authors.lastname: Allison
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK.
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Cooper
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Neale
mesh_terms: D050539:3-Isopropylmalate Dehydrogenase / Q000235:genetics; D000429:Alcohol Oxidoreductases / Q000235:genetics; D000619:Aminohydrolases / Q000235:genetics; D002843:Chromatin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015825:Chromosomes, Fungal / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D004706:Endodeoxyribonucleases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005800:Genes, Fungal / Q000235:genetics; D059765:Homologous Recombination / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008540:Meiosis / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011755:Pyrophosphatases / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000201:enzymology* / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000099257:Meiotic Recombination Protein SPO11
chemical_list: D050539:3-Isopropylmalate Dehydrogenase; D000429:Alcohol Oxidoreductases; D000619:Aminohydrolases; D002843:Chromatin; D004706:Endodeoxyribonucleases; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D011755:Pyrophosphatases; D029701:Saccharomyces cerevisiae Proteins; C092116:HIS4 protein, S cerevisiae; C524993:LEU2 protein, S cerevisiae; C513623:TEL1 protein, S cerevisiae; C518938:Spo11 protein, S cerevisiae; D000099257:Meiotic Recombination Protein SPO11