Protein Determinants of Meiotic DNA Break Hot Spots

Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Molecular cell (Impact Factor: 14.02). 02/2013; 49(5). DOI: 10.1016/j.molcel.2013.01.008
Source: PubMed


Meiotic recombination, crucial for proper chromosome segregation and genome evolution, is initiated by programmed DNA double-strand breaks (DSBs) in yeasts and likely all sexually reproducing species. In fission yeast, DSBs occur up to hundreds of times more frequently at special sites, called hot spots, than in other regions of the genome. What distinguishes hot spots from cold regions is an unsolved problem, although transcription factors determine some hot spots. We report the discovery that three coiled-coil proteins-Rec25, Rec27, and Mug20-bind essentially all hot spots with great specificity even without DSB formation. These small proteins are components of linear elements, are related to synaptonemal complex proteins, and are essential for nearly all DSBs at most hot spots. Our results indicate these hot spot determinants activate or stabilize the DSB-forming protein Rec12 (Spo11 homolog) rather than promote its binding to hot spots. We propose a paradigm for hot spot determination and crossover control by linear element proteins.

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Available from: Gerald R Smith, Aug 31, 2015
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    • "One way to rationalize these patterns is to hypothesize that the frequency of DSB repair with the sister vs. with the homolog depends on the fraction of DSBs in the interval that depend on the Rec25–Rec27–Mug20 complex. This complex binds loci to variable extents and, in hotspots, in proportion to DSB frequency (Fowler et al. 2013). Loci with a high population-average level of Rec25– Rec27–Mug20 bound also have a high frequency of DSBs (hotspots ) and are repaired primarily with the sister (IS repair) (Cromie et al. 2006; Hyppa and Smith 2010). "
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    ABSTRACT: Fission yeast Rec12 (Spo11 homolog) initiates meiotic recombination by forming developmentally programmed DNA double-strand breaks (DSBs). DSB distributions influence patterns of heredity and genome evolution, but the basis of the highly non-random choice of Rec12 cleavage sites is poorly understood, largely because available maps were of relatively low resolution and sensitivity. Here, we determined DSBs genome-wide at near-nucleotide resolution by sequencing the oligonucleotides attached to Rec12 following DNA cleavage. The single oligonucleotide size class allowed us to deeply sample all break events. We find strong evidence across the genome for differential DSB repair accounting for crossover invariance (constant cM/kb in spite of DSB hotspots). Surprisingly, about half of all crossovers occur in regions where DSBs occur at low frequency and are widely dispersed in location from cell to cell. These previously undetected, low-level DSBs thus play an outsized and crucial role in meiosis. We further find that the influence of underlying nucleotide sequence and chromosomal architecture differs in multiple ways from that in budding yeast. DSBs are not strongly restricted to nucleosome-depleted regions, as they are in budding yeast, but are nevertheless spatially influenced by chromatin structure. Our analyses demonstrate evolutionarily fluid factors contributing to crossover initiation and regulation.
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    Full-text · Article · Apr 2013 · Cell cycle (Georgetown, Tex.)
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    ABSTRACT: Meiotic homologous recombination is markedly activated during meiotic prophase to play central roles in faithful chromosome segregation and conferring genetic diversity to gametes. It is initiated by programmed DNA double-strand breaks (DSBs) by the conserved protein Spo11, and preferentially occurs at discrete sites called hotspots. Since the functions of Spo11 are influenced by both of local chromatin at hotspots and higher-order chromosome structures, formation of meiotic DSBs is under regulation of chromatin structure. Therefore, investigating features and roles of meiotic chromatin is crucial to elucidate the in vivo mechanism of meiotic recombination initiation. Recent progress in genome-wide chromatin analyses tremendously improved our understanding on this point, but many critical questions are left unaddressed. In this review, we summarize current knowledge in the field, and also discuss the future problems that must be solved to understand the role of chromatin structure in meiotic recombination.
    Preview · Article · Jun 2013 · Journal of Biochemistry
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