Meiotic double-strand breaks occur once per pair of (sister) chromatids and, via Mec1/ATR and Tel1/ATM, once per quartet of chromatids

Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2011; 108(50):20036-41. DOI: 10.1073/pnas.1117937108
Source: PubMed


Meiotic recombination initiates via programmed double-strand breaks (DSBs). We investigate whether, at a given initiation site, DSBs occur independently among the four available chromatids. For a single DSB "hot spot", the proportions of nuclei exhibiting zero, one, or two (or more) observable events were defined by tetrad analysis and compared with those predicted by different DSB distribution scenarios. Wild-type patterns are incompatible with independent distribution of DSBs among the four chromatids. In most or all nuclei, DSBs occur one-per-pair of chromatids, presumptively sisters. In many nuclei, only one DSB occurs per four chromatids, confirming the existence of trans inhibition where a DSB on one chromosome interactively inhibits DSB formation on the partner chromosome. Several mutants exhibit only a one-per-pair constraint, a phenotype we propose to imply loss of trans inhibition. Signal transduction kinases Mec1 (ATR) and Tel1 (ATM) exhibit this phenotype and thus could be mediators of this effect. Spreading trans inhibition can explain even spacing of total recombinational interactions and implies that establishment of interhomolog interactions and DSB formation are homeostatic processes. The two types of constraints on DSB formation provide two different safeguards against recombination failure during meiosis.

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Available from: Liangran Zhang, Sep 29, 2015
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    • "e as in cycling cells , and is then restored , dependent on Spo11 protein but independent of its role in DSBs ( Weiner and Kleckner 1994 ; Cha et al . 2000 ) . DSB - independent pairing interactions , before and during meiosis , may underlie ob - served trans effects of the homolog on DSB formation ( Xu and Kleckner 1995 ; Rocco and Nicolas 1996 ; Zhang et al . 2011 ) ."
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    ABSTRACT: Recombination is a prominent feature of meiosis in which it plays an important role in increasing genetic diversity during inheritance. Additionally, in most organisms, recombination also plays mechanical roles in chromosomal processes, most notably to mediate pairing of homologous chromosomes during prophase and, ultimately, to ensure regular segregation of homologous chromosomes when they separate at the first meiotic division. Recombinational interactions are also subject to important spatial patterning at both early and late stages. Recombination-mediated processes occur in physical and functional linkage with meiotic axial chromosome structure, with interplay in both directions, before, during, and after formation and dissolution of the synaptonemal complex (SC), a highly conserved meiosis-specific structure that links homolog axes along their lengths. These diverse processes also are integrated with recombination-independent interactions between homologous chromosomes, nonhomology-based chromosome couplings/clusterings, and diverse types of chromosome movement. This review provides an overview of these diverse processes and their interrelationships. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
    Cold Spring Harbor perspectives in biology 05/2015; 7(6). DOI:10.1101/cshperspect.a016626 · 8.68 Impact Factor
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    • "Separate but related to the question of why cells make a certain number of DSBs is how they ensure that the correct number is made. The DSB-forming machinery appears to be in excess over the DSBs actually formed (Neale et al. 2005; Milman et al. 2009; Lange et al. 2011), implying the existence of feedback mechanisms that influence SPO11 activity (Joyce et al. 2011; Lange et al. 2011; Zhang et al. 2011). However, it has been unclear how such feedback is integrated with meiotic chromosome dynamics. "
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    Genes & development 04/2013; 27(8). DOI:10.1101/gad.213652.113 · 10.80 Impact Factor
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    ABSTRACT: Humans suffer from high rates of fetal aneuploidy, often arising from the absence of meiotic crossover recombination between homologous chromosomes. Meiotic recombination is initiated by double-strand breaks (DSBs) generated by the SPO11 transesterase. In yeast and worms, at least one buffering mechanism, crossover homeostasis, maintains crossover numbers despite variation in DSB numbers. We show here that mammals exhibit progressive homeostatic control of recombination. In wild-type mouse spermatocytes, focus numbers for early recombination proteins (RAD51, DMC1) were highly variable from cell to cell, whereas foci of the crossover marker MLH1 showed little variability. Furthermore, mice with greater or fewer copies of the Spo11 gene--with correspondingly greater or fewer numbers of early recombination foci--exhibited relatively invariant crossover numbers. Homeostatic control is enforced during at least two stages, after the formation of early recombination intermediates and later while these intermediates mature towards crossovers. Thus, variability within the mammalian meiotic program is robustly managed by homeostatic mechanisms to control crossover formation, probably to suppress aneuploidy. Meiotic recombination exemplifies how order can be progressively implemented in a self-organizing system despite natural cell-to-cell disparities in the underlying biochemical processes.
    Nature Cell Biology 03/2012; 14(4):424-30. DOI:10.1038/ncb2451 · 19.68 Impact Factor
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