Synapsis-Defective Mutants Reveal a Correlation Between Chromosome Conformation and the Mode of Double-Strand Break Repair During<i>Caenorhabditis elegans</i>Meiosis

Smolikov, Sarit; Eizinger, Andreas; Hurlburt, Allison; Rogers, Eric; Villeneuve, Anne M.; Colaiácovo, Mónica P.

doi:10.1534/genetics.107.076968

Cited by 81 publications

(114 citation statements)

References 27 publications

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“…In hermaphrodites, failure in chromosome synapsis activates the recombination checkpoint pathway leading to increased levels of apoptosis due to the absence of a homologous partner for repair of DSBs (MacQueen et al 2002;Colaiácovo et al 2003;Smolikov et al 2007Smolikov et al , 2009. As the male X chromosome has no homologous chromosome to repair DSBs and fails to activate the apoptotic pathway even in an oogenic germ line [fem-3(lf) X0, Figure 2A, Table 1], we reasoned that the single X chromosome does not incur DSBs.…”

Section: Resultsmentioning

confidence: 99%

“…In mutant hermaphrodite germ lines that are unable to repair breaks due to unavailability of the homologous chromosome there is an apparent global increase in the number of DSBs as well as a persistence of breaks on all chromosomes into late stages of pachytene (Colaiácovo et al 2003;Carlton et al 2006;Smolikov et al 2007Smolikov et al , 2009). To determine whether DSBs on the single X chromosome in N2 males also had this effect, we examined the global appearance and removal of RAD-51 in male and hermaphrodite germ lines.…”

Section: Resultsmentioning

confidence: 99%

“…Surprisingly, progeny from rec-8 hermaphrodites mated to wild-type males have a high hatch rate (89%) while only 16% of embryos hatch when the sperm come from rec-8 males (Severson et al 2009). Mutations that disrupt chromosome synapsis or recombinational repair in either hermaphrodites or males result in extensive embryonic lethality, but only the adult hermaphrodite germ line responds by inducing apoptosis (MacQueen et al 2002;Alpi et al 2003;Colaiácovo et al 2003;Smolikov et al 2007Smolikov et al , 2009). Perhaps, a lengthier prophase in hermaphrodites gives the germ line time to launch a checkpoint response, which allows for DNA damage repair, or to remove defective germ cells.…”

Section: Discussionmentioning

confidence: 99%

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A Single Unpaired and Transcriptionally Silenced X Chromosome Locally Precludes Checkpoint Signaling in theCaenorhabditis elegansGerm Line

Jaramillo-Lambert

Engebrecht

2010

Genetics

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In many organisms, female and male meiosis display extensive sexual dimorphism in the temporal meiotic program, the number and location of recombination events, sex chromosome segregation, and checkpoint function. We show here that both meiotic prophase timing and germ-line apoptosis, one output of checkpoint signaling, are dictated by the sex of the germ line (oogenesis vs. spermatogenesis) in Caenorhabditis elegans. During oogenesis in feminized animals ( fem-3), a single pair of asynapsed autosomes elicits a checkpoint response, yet an unpaired X chromosome fails to induce checkpoint activation. The single X in males and fem-3 worms is a substrate for the meiotic recombination machinery and repair of the resulting double strand breaks appears to be delayed compared with worms carrying paired X chromosomes. Synaptonemal complex axial HORMA domain proteins, implicated in repair of meiotic double strand breaks (DSBs) and checkpoint function, are assembled and disassembled on the single X similarly to paired chromosomes, but the central region component, SYP-1, is not loaded on the X chromosome in males. In fem-3 worms some X chromosomes achieve nonhomologous self-synapsis; however, germ cells with SYP-1-positive X chromosomes are not preferentially protected from apoptosis. Analyses of chromatin and X-linked gene expression indicate that a single X, unlike asynapsed X chromosomes or autosomes, maintains repressive chromatin marks and remains transcriptionally silenced and suggests that this state locally precludes checkpoint signaling.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A Single Unpaired and Transcriptionally Silenced X Chromosome Locally Precludes Checkpoint Signaling in theCaenorhabditis elegansGerm Line

Jaramillo-Lambert

Engebrecht

2010

Genetics

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“…There are only a few cases in other organisms where defects in meiotic DSB repair have been shown to result in elevated use of NHEJ. In Caenorhabditis elegans, NHEJ has been shown to participate in meiotic DSB repair in either brc-2 mutants, where homologous recombination is impaired due to misregulation of RAD-51, or in a double mutant combination: one affecting the SC (syp-3) and the other affecting sister chromatid cohesion (rec-8) (Martin et al 2005;Smolikov et al 2007). All three studies may be revealing genes with regulatory functions in DSB repair and crossover formation.…”

Section: Discussionmentioning

confidence: 99%

Multiple Barriers to Nonhomologous DNA End Joining During Meiosis inDrosophila

Joyce¹,

Paul

Chen

et al. 2012

Genetics

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Repair of meiotic double-strand breaks (DSBs) uses the homolog and recombination to yield crossovers while alternative pathways such as nonhomologous end joining (NHEJ) are suppressed. Our results indicate that NHEJ is blocked at two steps of DSB repair during meiotic prophase: first by the activity of the MCM-like protein MEI-218, which is required for crossover formation, and, second, by Rad51-related proteins SPN-B (XRCC3) and SPN-D (RAD51C), which physically interact and promote homologous recombination (HR). We further show that the MCM-like proteins also promote the activity of the DSB repair checkpoint pathway, indicating an early requirement for these proteins in DSB processing. We propose that when a meiotic DSB is formed in the absence of both MEI-218 and SPN-B or SPN-D, a DSB substrate is generated that can enter the NHEJ repair pathway. Indeed, due to its high error rate, multiple barriers may have evolved to prevent NHEJ activity during meiosis.

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“…Several features make this an interesting system for investigating factors that promote and/or inhibit COs during meiosis. First, essentially all COs in C. elegans depend on conserved meiotic CO-promoting machinery (i.e., Msh4 and Msh5) and on SC central region proteins (SYP-1, -2, -3, and -4), so analysis is generally not complicated by residual COs forming by alternative pathways (Zalevsky et al 1999;Kelly et al 2000;MacQueen et al 2002;Colaiacovo et al 2003;Smolikov et al 2007aSmolikov et al , 2009. Second, C. elegans hermaphrodites exhibit robust CO control, with COs usually being limited to one per homolog pair per meiosis (Hillers and Villeneuve 2003;Nabeshima et al 2004;Hammarlund et al 2005).…”

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confidence: 99%

The Synaptonemal Complex Shapes the Crossover Landscape Through Cooperative Assembly, Crossover Promotion and Crossover Inhibition During Caenorhabditis elegans Meiosis

2010

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The synaptonemal complex (SC) is a highly ordered proteinaceous structure that assembles at the interface between aligned homologous chromosomes during meiotic prophase. The SC has been demonstrated to function both in stabilization of homolog pairing and in promoting the formation of interhomolog crossovers (COs). How the SC provides these functions and whether it also plays a role in inhibiting CO formation has been a matter of debate. Here we provide new insight into assembly and function of the SC by investigating the consequences of reducing (but not eliminating) SYP-1, a major structural component of the SC central region, during meiosis in Caenorhabditis elegans. First, we find an increased incidence of double CO (DCO) meiotic products following partial depletion of SYP-1 by RNAi, indicating a role for SYP-1 in mechanisms that normally limit crossovers to one per homolog pair per meiosis. Second, syp-1 RNAi worms exhibit both a strong preference for COs to occur on the left half of the X chromosome and a significant bias for SYP-1 protein to be associated with the left half of the chromosome, implying that the SC functions locally in promoting COs. Distribution of SYP-1 on chromosomes in syp-1 RNAi germ cells provides strong corroboration for cooperative assembly of the SC central region and indicates that SYP-1 preferentially associates with X chromosomes when it is present in limiting quantities. Further, the observed biases in the distribution of both COs and SYP-1 protein support models in which synapsis initiates predominantly in the vicinity of pairing centers (PCs). However, discontinuities in SC structure and clear gaps between localized foci of PC-binding protein HIM-8 and X chromosome-associated SYP-1 stretches allow refinement of models for the role of PCs in promoting synapsis. Our data suggest that the CO landscape is shaped by a combination of three attributes of the SC central region: a CO-promoting activity that functions locally at CO sites, a cooperative assembly process that enables CO formation in regions distant from prominent sites of synapsis initiation, and CO-inhibitory role(s) that limit CO number.

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Synapsis-Defective Mutants Reveal a Correlation Between Chromosome Conformation and the Mode of Double-Strand Break Repair DuringCaenorhabditis elegansMeiosis

Cited by 81 publications

References 27 publications

A Single Unpaired and Transcriptionally Silenced X Chromosome Locally Precludes Checkpoint Signaling in theCaenorhabditis elegansGerm Line

A Single Unpaired and Transcriptionally Silenced X Chromosome Locally Precludes Checkpoint Signaling in theCaenorhabditis elegansGerm Line

Multiple Barriers to Nonhomologous DNA End Joining During Meiosis inDrosophila

The Synaptonemal Complex Shapes the Crossover Landscape Through Cooperative Assembly, Crossover Promotion and Crossover Inhibition During Caenorhabditis elegans Meiosis

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