Homologue engagement controls meiotic DNA break number and distribution.
Meiotic recombination promotes genetic diversification as well as pairing and segregation of homologous chromosomes, but the double-strand breaks (DSBs) that initiate recombination are dangerous lesions that can cause mutation or meiotic failure. How cells control DSBs to balance between beneficial and deleterious outcomes is not well understood. Here we test the hypothesis that DSB control involves a network of intersecting negative regulatory circuits. Using multiple complementary methods, we show that DSBs form in greater numbers in Saccharomyces cerevisiae cells lacking ZMM proteins, a suite of recombination-promoting factors traditionally regarded as acting strictly downstream of DSB formation. ZMM-dependent DSB control is genetically distinct from a pathway tying break formation to meiotic progression through the Ndt80 transcription factor. These counterintuitive findings suggest that homologous chromosomes that have successfully engaged one another stop making breaks. Genome-wide DSB maps uncover distinct responses by different subchromosomal domains to the ZMM mutation zip3 (also known as cst9), and show that Zip3 is required for the previously unexplained tendency of DSB density to vary with chromosome size. Thus, feedback tied to ZMM function contributes in unexpected ways to spatial patterning of recombination.
1] Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Weill Graduate School of Medical Sciences of Cornell University, New York, New York 10065, USA.
Drew
D
Thacker
1] Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Neeman
N
Mohibullah
1] Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Weill Graduate School of Medical Sciences of Cornell University, New York, New York 10065, USA.
Xuan
X
Zhu
1] Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Weill Graduate School of Medical Sciences of Cornell University, New York, New York 10065, USA [3] Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Scott
S
Keeney
D023902:Chromosome Pairing / Q000235:genetics*; D015825:Chromosomes, Fungal / Q000235:genetics* / Q000378:metabolism*; D003434:Crossing Over, Genetic / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000378:metabolism; D004843:Epistasis, Genetic; D016681:Genome, Fungal / Q000235:genetics; D059765:Homologous Recombination / Q000235:genetics*; D008540:Meiosis / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
D004268:DNA-Binding Proteins; C097071:NDT80 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; C523917:Zip3 protein, S cerevisiae