Antagonistic roles of ubiquitin ligase HEI10 and SUMO ligase RNF212 regulate meiotic recombination

Qiao, Huanyu; Rao, H.B.D. Prasada; Yang, Ye; Fong, Jared; Cloutier, Jeffrey M.; Deacon, Dekker C.; Nagel, Kathryn; Swartz, Rebecca K; Strong, Edward; Holloway, J. Kim; Cohen, Paula E.; Schimenti, John C.; Ward, Jeremy O.; Hunter, Neil

doi:10.1038/ng.2858

Cited by 181 publications

(291 citation statements)

References 29 publications

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“…Thus, the basic findings upon which the two-round scenario is based can be explained just as easily by the one-round zygotene scenario seen in Sordaria. Notably, also, in mouse, Msh4 foci and SC nucleations strongly colocalize at zygotene, as is consistent with earlier specification of Msh4 focus patterns in local coordination with SC nucleation (35,36).…”

Section: Complex Spatial Patterns Can Arise In a Single Interference-supporting

confidence: 88%

Interference-mediated synaptonemal complex formation with embedded crossover designation

Zhang

Espagne

Muyt

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Biological systems exhibit complex patterns at length scales ranging from the molecular to the organismic. Along chromosomes, events often occur stochastically at different positions in different nuclei but nonetheless tend to be relatively evenly spaced. Examples include replication origin firings, formation of chromatin loops along chromosome axes and, during meiosis, localization of crossover recombination sites ("crossover interference"). We present evidence in the fungus Sordaria macrospora that crossover interference is part of a broader pattern that includes synaptonemal complex (SC) nucleation. This pattern comprises relatively evenly spaced SC nucleation sites, among which a subset are crossover sites that show a classical interference distribution. This pattern ensures that SC forms regularly along the entire length of the chromosome as required for the maintenance of homolog pairing while concomitantly having crossover interactions locally embedded within the SC structure as required for both DNA recombination and structural events of chiasma formation. This pattern can be explained by a threshold-based designation and spreading interference process. This model can be generalized to give diverse types of related and/or partially overlapping patterns, in two or more dimensions, for any type of object.spatial patterning | synapsis initiation site | recombination/synapsis | crossover designation M eiosis is the specialized cellular cycle that yields haploid gametes for sexual reproduction. A central feature of the meiotic program is recombination (1, 2). DNA/DNA recombination interactions, initiated by programmed double-strand breaks (DSBs), mediate the recognition and juxtaposition (pairing) of homologous chromosomes. A minority subset of these interactions matures into reciprocal crossover recombination products (COs); the remaining majority matures primarily into interhomolog non-crossover products (NCOs). COs promote genetic diversity but also are required for the segregation of homologous chromosomes (homologs) via their role in creating chiasmata (3).A nearly universal feature of meiosis is that COs occur along a particular chromosome at different positions in different meiotic nuclei. Nonetheless, along any given chromosome, COs tend to be evenly spaced. This pattern results from the reduced possibility that a second cross-over will occur if a crossover has occurred nearby. The existence of such a pattern was identified more than a century ago as the genetic phenomenon of CO interference (4, 5). In this phenomenon, occurrence of a CO in one genetic interval is accompanied by a reduced probability that another CO will occur along the same chromosome in a nearby interval. This effect implies the existence of communication along chromosomes, with an event at one position triggering occurrence of an "interference signal" that spreads outward, inhibiting occurrence of subsequent events nearby.A second central feature of the meiotic program is the synaptonemal complex (SC). This prominent structure link...

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Section: Complex Spatial Patterns Can Arise In a Single Interference-supporting

confidence: 88%

Interference-mediated synaptonemal complex formation with embedded crossover designation

Zhang

Espagne

Muyt

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Meiotic stages are defined by chromosome structure and SC morphology (Zickler and Kleckner 1999). Studies in mice frequently use the morphology of the SC and chromosome morphology (by DAPI staining), based on examination of immunofluorescence preparation, as an indication of the meiotic stage of germline nuclei (Cole et al 2012;Kauppi et al 2013;Qiao et al 2014). We adopted this metric to investigate meiotic progression in kin-18 mutants.…”

Section: Kin-18 Is Required For Normal Meiotic Progression In C Elegansmentioning

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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“…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). The CO designation process is tightly regulated, yielding a highly nonrandom distribution in which a relatively small number of CO-based connections are formed between homologs, yet chromosome pairs lacking such connections are extremely rare.…”

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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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Antagonistic roles of ubiquitin ligase HEI10 and SUMO ligase RNF212 regulate meiotic recombination

Cited by 181 publications

References 29 publications

Interference-mediated synaptonemal complex formation with embedded crossover designation

Interference-mediated synaptonemal complex formation with embedded crossover designation

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

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

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