Regulating double-stranded DNA break repair towards crossover or non-crossover during mammalian meiosis

Baudat, Frédéric; Massy, Bernard de

doi:10.1007/s10577-007-1140-3

Cited by 191 publications

(214 citation statements)

References 94 publications

(90 reference statements)

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“…This process is initiated by the pairing of homologous chromosomes (homologs) and subsequent double-strand break (DSB)-mediated recombination (Neale and Keeney 2006;Baudat and de Massy 2007). A number of mechanisms are involved in chromosome pairing and alignment.…”

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confidence: 99%

Meiosis-specific cohesin mediates homolog recognition in mouse spermatocytes

Ishiguro¹,

et al. 2014

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During meiosis, homologous chromosome (homolog) pairing is promoted by several layers of regulation that include dynamic chromosome movement and meiotic recombination. However, the way in which homologs recognize each other remains a fundamental issue in chromosome biology. Here, we show that homolog recognition or association initiates upon entry into meiotic prophase before axis assembly and double-strand break (DSB) formation. This homolog association develops into tight pairing only during or after axis formation. Intriguingly, the ability to recognize homologs is retained in Sun1 knockout spermatocytes, in which telomere-directed chromosome movement is abolished, and this is the case even in Spo11 knockout spermatocytes, in which DSB-dependent DNA homology search is absent. Disruption of meiosis-specific cohesin RAD21L precludes the initial association of homologs as well as the subsequent pairing in spermatocytes. These findings suggest the intriguing possibility that homolog recognition is achieved primarily by searching for homology in the chromosome architecture as defined by meiosis-specific cohesin rather than in the DNA sequence itself.

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confidence: 99%

Meiosis-specific cohesin mediates homolog recognition in mouse spermatocytes

Ishiguro¹,

et al. 2014

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“…Recent evidence suggests that checkpoint-like feedback mechanisms operate to ensure both that DSB formation continues until each homolog pair has at least one CO-eligible recombination intermediate and that DSB formation will shut down once this condition is met Stamper et al 2013). Following DSB formation, a subset of the initial recombination intermediates is selected to become COs, recruiting a cohort of CO-promoting (pro-CO) proteins that function to stabilize and protect these COdesignated intermediates (Baudat and De Massy 2007;Kohl and Sekelsky 2013;Lynn et al 2007). A widely conserved solution for protecting potential CO intermediates involves the MutSg complex, comprising MSH4 and MSH5, meiosisspecific members of the MutS protein family that can form a sliding clamp on DNA in response to recognition of branched DNA structures (Baudat and De Massy 2007;Lynn et al 2007;Snowden et al 2004).…”

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confidence: 99%

“…Following DSB formation, a subset of the initial recombination intermediates is selected to become COs, recruiting a cohort of CO-promoting (pro-CO) proteins that function to stabilize and protect these COdesignated intermediates (Baudat and De Massy 2007;Kohl and Sekelsky 2013;Lynn et al 2007). A widely conserved solution for protecting potential CO intermediates involves the MutSg complex, comprising MSH4 and MSH5, meiosisspecific members of the MutS protein family that can form a sliding clamp on DNA in response to recognition of branched DNA structures (Baudat and De Massy 2007;Lynn et al 2007;Snowden et al 2004). In many organisms, MutSg is initially recruited to multiple sites in excess of eventual COs, but it becomes stabilized at only a subset of these sites through recruitment of other pro-CO factors (Kneitz et al 2000;Yokoo et al 2012;Reynolds et al 2013;Holloway et al 2014;Qiao et al 2014).…”

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confidence: 99%

DNA Helicase HIM-6/BLM Both Promotes MutSγ-Dependent Crossovers and Antagonizes MutSγ-Independent Interhomolog Associations During Caenorhabditis elegans Meiosis

et al. 2014

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Meiotic recombination is initiated by the programmed induction of double-strand DNA breaks (DSBs), lesions that pose a potential threat to the genome. A subset of the DSBs induced during meiotic prophase become designated to be repaired by a pathway that specifically yields interhomolog crossovers (COs), which mature into chiasmata that temporarily connect the homologs to ensure their proper segregation at meiosis I. The remaining DSBs must be repaired by other mechanisms to restore genomic integrity prior to the meiotic divisions. Here we show that HIM-6, the Caenorhabditis elegans ortholog of the RecQ family DNA helicase BLM, functions in both of these processes. We show that him-6 mutants are competent to load the MutSg complex at multiple potential CO sites, to generate intermediates that fulfill the requirements of monitoring mechanisms that enable meiotic progression, and to accomplish and robustly regulate CO designation. However, recombination events at a subset of CO-designated sites fail to mature into COs and chiasmata, indicating a pro-CO role for HIM-6/BLM that manifests itself late in the CO pathway. Moreover, we find that in addition to promoting COs, HIM-6 plays a role in eliminating and/or preventing the formation of persistent MutSg-independent associations between homologous chromosomes. We propose that HIM-6/BLM enforces biased outcomes of recombination events to ensure that both (a) CO-designated recombination intermediates are reliably resolved as COs and (b) other recombination intermediates reliably mature into noncrossovers in a timely manner.

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“…Interference might then be the signature of a mechanism allowing for the appearance of an obligate CO followed by suppression of CO formation in favor of NCOs. Such an interpretation is supported by the fact that most organisms produce far more DSBs than COs (Baudat and De Massy 2007), so that high interference strengths probably reflect selection pressures to control the number of COs. Interference is thus integral to a mechanistic understanding of meiosis, and it comes as no surprise that most organisms that have been studied do exhibit CO interference.…”

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Hot Regions of Noninterfering Crossovers Coexist with a Nonuniformly Interfering Pathway inArabidopsis thaliana

et al. 2013

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In most organisms that have been studied, crossovers formed during meiosis exhibit interference: nearby crossovers are rare. Here we provide an in-depth study of crossover interference in Arabidopsis thaliana, examining crossovers genome-wide in .1500 backcrosses for both male and female meiosis. This unique data set allows us to take a two-pathway modeling approach based on superposing a fraction p of noninterfering crossovers and a fraction (1 2 p) of interfering crossovers generated using the gamma model characterized by its interference strength nu. Within this framework, we fit the two-pathway model to the data and compare crossover interference strength between chromosomes and then along chromosomes. We find that the interfering pathway has markedly higher interference strength nu in female than in male meiosis and also that male meiosis has a higher proportion p of noninterfering crossovers. Furthermore, we test for possible intrachromosomal variations of nu and p. Our conclusion is that there are clear differences between left and right arms as well as between central and peripheral regions. Finally, statistical tests unveil a genome-wide picture of small-scale heterogeneities, pointing to the existence of hot regions in the genome where crossovers form preferentially without interference. SEXUALLY reproducing organisms undergo meiosis, thereby producing gametes having a level of ploidy equal to half that of the parental cells. This reduction in ploidy emerges from a complex and tightly controlled sequence of events. In most organisms, prophase I of meiosis begins by the active formation of double-strand breaks (DSBs) mediated by Spo11, a topoisomerase-like transesterase (Keeney et al. 1997). Then homologous chromosomes align and pair as the DSBs are repaired, typically using a homolog as template. Such DSB repairs can lead to either a crossover (CO), a reciprocal exchange of large chromosomal fragments between homologs), or to a noncrossover (NCO), a nonreciprocal exchange of small chromosomal segments between homologs, detected through associated gene conversions (Bishop and Zickler 2004)). COs mediate intrachromosomal rearrangement of parental alleles, giving rise to novel haplotypes in the gametes and thus driving genetic diversity. They also provide a physical connection between the homologs, holding them in a stable pair (bivalent) and allowing their correct segregation during anaphase I (Page and Hawley 2004;Jones and Franklin 2006). Studies in several plants and animals have shown that the average number of COs in meiosis may vary between male and female meiosis (see review by Lenormand and Dutheil 2005), but there is no general rule that governs the direction or degree of CO number variation. Similarly, the distribution of COs along chromosomes can also differ when comparing male and female meiosis (Drouaud et al. 2007). Such distributions are generally nonuniform: some portions of the physical chromosome seem more likely to recombine while others hardly ever do (e.g., close to the cent...

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Regulating double-stranded DNA break repair towards crossover or non-crossover during mammalian meiosis

Cited by 191 publications

References 94 publications

Meiosis-specific cohesin mediates homolog recognition in mouse spermatocytes

Meiosis-specific cohesin mediates homolog recognition in mouse spermatocytes

DNA Helicase HIM-6/BLM Both Promotes MutSγ-Dependent Crossovers and Antagonizes MutSγ-Independent Interhomolog Associations During Caenorhabditis elegans Meiosis

Hot Regions of Noninterfering Crossovers Coexist with a Nonuniformly Interfering Pathway inArabidopsis thaliana

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