The C. elegans DSB-2 Protein Reveals a Regulatory Network that Controls Competence for Meiotic DSB Formation and Promotes Crossover Assurance

Rosu, Simona; Zawadzki, Karl A.; Stamper, Ericca L.; Libuda, Diana E.; Reese, Angela L.; Dernburg, Abby F.; Villeneuve, Anne M.

doi:10.1371/journal.pgen.1003674

Cited by 151 publications

(276 citation statements)

References 58 publications

(119 reference statements)

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“…The X chromosome of males is the only chromosome not subject to ATM-1-dependent feedback mechanisms at the level of DSB formation Recent studies have uncovered feedback mechanisms proposed to monitor homolog pairing and DSB formation and to ensure timely CO formation (Barchi et al 2008;Carballo et al 2013;Kauppi et al 2013;Rosu et al 2013;Stamper et al 2013). We speculated that in the heterogametic sex, such feedback mechanisms are altered to handle the challenges of a constitutively unpaired chromosome.…”

Section: Resultsmentioning

confidence: 99%

Pseudosynapsis and Decreased Stringency of Meiotic Repair Pathway Choice on the Hemizygous Sex Chromosome of Caenorhabditis elegans Males

Checchi¹,

Lawrence

Van

et al. 2014

Genetics

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During meiosis, accurate chromosome segregation relies on homology to mediate chromosome pairing, synapsis, and crossover recombination. Crossovers are dependent upon formation and repair of double-strand breaks (DSBs) by homologous recombination (HR). In males of many species, sex chromosomes are largely hemizygous, yet DSBs are induced along nonhomologous regions. Here we analyzed the genetic requirements for meiotic DSB repair on the completely hemizygous X chromosome of Caenorhabditis elegans males. Our data reveal that the kinetics of DSB formation, chromosome pairing, and synapsis are tightly linked in the male germ line. Moreover, DSB induction on the X is concomitant with a brief period of pseudosynapsis that may allow X sister chromatids to masquerade as homologs. Consistent with this, neither meiotic kleisins nor the SMC-5/6 complex are essential for DSB repair on the X. Furthermore, early processing of X DSBs is dependent on the CtIP/Sae2 homolog COM-1, suggesting that as with paired chromosomes, HR is the preferred pathway. In contrast, the X chromosome is refractory to feedback mechanisms that ensure crossover formation on autosomes. Surprisingly, neither RAD-54 nor BRC-2 are essential for DSB repair on the X, suggesting that unlike autosomes, the X is competent for repair in the absence of HR. When both RAD-54 and the structure-specific nuclease XPF-1 are abrogated, X DSBs persist, suggesting that single-strand annealing is engaged in the absence of HR. Our findings indicate that alteration in sister chromatid interactions and flexibility in DSB repair pathway choice accommodate hemizygosity on sex chromosomes.

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Section: Resultsmentioning

confidence: 99%

Pseudosynapsis and Decreased Stringency of Meiotic Repair Pathway Choice on the Hemizygous Sex Chromosome of Caenorhabditis elegans Males

Checchi¹,

Lawrence

Van

et al. 2014

Genetics

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“…In wild-type germ lines, RAD-51 foci are abundant in earlymid-pachytene nuclei and then decline and disappear from most nuclei by late pachytene (Alpi et al 2003;Colaiacovo et al 2003;Rosu et al 2013;and Figure S1). MSH-5 is first detected as faint foci in early pachytene nuclei; MSH-5 foci become brighter and more abundant during mid-pachytene and then decline in number upon transition to late pachytene, where their localization becomes restricted to designated CO sites (Yokoo et al 2012 and Figure S1).…”

Section: Resultsmentioning

confidence: 99%

“…Markers of meiotic progression appear normal in him-6 mutants: Several recent studies have provided evidence for a checkpoint-like negative feedback network that operates during C. elegans meiosis to couple multiple aspects of meiotic prophase progression to the formation of crossovereligible recombination intermediates (Rosu et al 2011;Rosu et al 2013;Stamper et al 2013;Woglar et al 2013). These Figure 3 Timely transition in pachytene progression in the him-6 mutant.…”

Section: Resultsmentioning

confidence: 99%

“…For these analyses, gonads were dissected and fixed 20-24 hr post-L4 stage. For images in Figure 3, immunofluorescence and imaging were conducted as in Nabeshima et al (2004), with minor modifications as described in Rosu et al (2013), using worms dissected and fixed at 48 hr post-L4. Extent of the SUN-1 S8Pi-positive zone was quantified as in MlynarczykEvans et al (2013).…”

Section: Cytological Analysesmentioning

confidence: 99%

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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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“…Signaling from MPK-1-activated nuclei (mid-pachytene) to DSB formation (early pachytene) may not be very challenging since these nuclei are positioned relatively close to each other. The idea that downstream meiotic events can affect early meiotic events is plausible based on recent findings; crossover formation or complete synapsis (a later meiotic event) can signal to affect the number of DSB formed (early meiotic event) (e.g., Kauppi et al 2013;Rosu et al 2013). This model suggests that feedback loops communicate the progression of late meiotic events to regulate early meiotic events.…”

mentioning

confidence: 99%

Coordination of Recombination with Meiotic Progression in the Caenorhabditis elegans Germline by KIN-18, a TAO Kinase That Regulates the Timing of MPK-1 Signaling

Yin¹,

Donlevy²,

Smolikove

2015

Genetics

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Meiosis is a tightly regulated process requiring coordination of diverse events. A conserved ERK/MAPK-signaling cascade plays an essential role in the regulation of meiotic progression. The Thousand And One kinase (TAO) kinase is a MAPK kinase kinase, the meiotic role of which is unknown. We have analyzed the meiotic functions of KIN-18, the homolog of mammalian TAO kinases, in Caenorhabditis elegans. We found that KIN-18 is essential for normal meiotic progression; mutants exhibit accelerated meiotic recombination as detected both by analysis of recombination intermediates and by crossover outcome. In addition, ectopic germ-cell differentiation and enhanced levels of apoptosis were observed in kin-18 mutants. These defects correlate with ectopic activation of MPK-1 that includes premature, missing, and reoccurring MPK-1 activation. Late progression defects in kin-18 mutants are suppressed by inhibiting an upstream activator of MPK-1 signaling, KSR-2. However, the acceleration of recombination events observed in kin-18 mutants is largely MPK-1-independent. Our data suggest that KIN-18 coordinates meiotic progression by modulating the timing of MPK-1 activation and the progression of recombination events. The regulation of the timing of MPK-1 activation ensures the proper timing of apoptosis and is required for the formation of functional oocytes. Meiosis is a conserved process; thus, revealing that KIN-18 is a novel regulator of meiotic progression in C. elegans would help to elucidate TAO kinase's role in germline development in higher eukaryotes.KEYWORDS KIN-18; MPK-1; TAO; meiosis; recombination; genetics of sex T HE germline contains a multitude of cells that proliferate to form a population that will undergo two meiotic divisions, giving rise to gametes. In meiosis, one round of DNA replication is followed by two cell divisions reducing the ploidy of the germ cell by half. A large fraction of the cells encompassing the germline are found in meiotic prophase I. Many of the key evolutionarily conserved events that take place in this specialized prophase are aimed at preparing chromosomes for their segregation in meiosis I. One such essential and conserved event is the formation of crossovers between homologous chromosomes. During the initial stages of meiotic prophase I (leptotene/zygotene), a protein structure named the synaptonemal complex (SC) starts to assemble between homologs (MacQueen et al. 2002;Schild-Prufert et al. 2011). Concurrently, meiotic DNA double-strand breaks (DSBs) are introduced to initiate meiotic recombination (Keeney et al. 1997;Dernburg et al. 1998). As meiosis progresses, germ cells enter pachytene where the SC is fully formed and meiotic DSBs are processed and repaired. In the presence of a fully formed SC, meiotic DSBs are repaired, giving rise to crossovers by late pachytene. In most multicellular organisms, apoptosis is activated in late pachytene and reduces the number of germ cells in the developing germline (Gumienny et al. 1999). Apoptosis serves as a quality control...

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The C. elegans DSB-2 Protein Reveals a Regulatory Network that Controls Competence for Meiotic DSB Formation and Promotes Crossover Assurance

Cited by 151 publications

References 58 publications

Pseudosynapsis and Decreased Stringency of Meiotic Repair Pathway Choice on the Hemizygous Sex Chromosome of Caenorhabditis elegans Males

Pseudosynapsis and Decreased Stringency of Meiotic Repair Pathway Choice on the Hemizygous Sex Chromosome of Caenorhabditis elegans Males

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

Coordination of Recombination with Meiotic Progression in the Caenorhabditis elegans Germline by KIN-18, a TAO Kinase That Regulates the Timing of MPK-1 Signaling

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