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

Schvarzstein, Mara; Pattabiraman, Divya; Libuda, Diana E.; Ramadugu, Ajit; Tam, Angela; Martínez-Pérez, Enrique; Roelens, Baptiste; Zawadzki, Karl A.; Yokoo, Rayka; Rosu, Simona; Severson, Aaron F.; Meyer, Barbara J; Nabeshima, Kentaro; Villeneuve, Anne M.

doi:10.1534/genetics.114.161513

Cited by 33 publications

(60 citation statements)

References 56 publications

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“…1). Similar inferences have been made for the C. elegans BLM ortholog, HIM-6 (Schvarzstein et al 2014). Consistent with this conclusion, in budding yeast, the high levels of crossovers seen when all three structure-selective endonucleases (Mus81 -Mms4, Slx1 -Slx4 and Yen1) are absent are dependent on both MutLg and Sgs1 (De Muyt et al 2012;Zakharyevich et al 2012).…”

Section: The Str/btr Ensembles Are Master Regulators Of Meiotic Jointsupporting

confidence: 79%

Meiotic Recombination: The Essence of Heredity

Hunter

2015

Cold Spring Harb Perspect Biol

694

869

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The study of homologous recombination has its historical roots in meiosis. In this context, recombination occurs as a programmed event that culminates in the formation of crossovers, which are essential for accurate chromosome segregation and create new combinations of parental alleles. Thus, meiotic recombination underlies both the independent assortment of parental chromosomes and genetic linkage. This review highlights the features of meiotic recombination that distinguish it from recombinational repair in somatic cells, and how the molecular processes of meiotic recombination are embedded and interdependent with the chromosome structures that characterize meiotic prophase. A more in-depth review presents our understanding of how crossover and noncrossover pathways of meiotic recombination are differentiated and regulated. The final section of this review summarizes the studies that have defined defective recombination as a leading cause of pregnancy loss and congenital disease in humans. MEIOSIS AND THE ROOTS OF RECOMBINATION RESEARCHT he concept of recombination emerged during the early 20th century, following the post-Mendel era of heredity research. Thomas Hunt Morgan's formal theory of gene linkage and crossing-over (Morgan 1913) was a synthesis of three key concepts: "the chromosome theory of inheritance," imparted by Wilhelm Roux, Walther Flemming, Theodor Boveri, and Walter Sutton; "gene linkage," an exception to Mendel's law of independent assortment, first reported by Carl Correns; and the "chiasmatype theory," derived from Frans Janssens' cytological observations of meiotic chromosomes. The first proof of the crossover theory came from Harriet Creighton and Barbara McClintock (Creighton and McClintock 1931), who were able to correlate cytological and genetic exchanges in maize.Experiments aimed at understanding the mechanism of meiotic recombination became dominated by fungal genetics because of the huge advantage afforded by being able to recover all four meiotic products. These elegant studies culminated in four key concepts that formed the foundation of molecular models of recombination: gene conversion, an exception to Mendel's principle of segregation, signaled a local nonreciprocal transfer of genetic information (Winkler 1930;Lindergren 1953;Mitchell 1955); postmeiotic segregation (PMS) indicated the presence of heteroduplex DNA (Olive 1959;Kitani et al. 1962) (Lissouba and Rizet 1960;Murray 1960); and the strong correlation between gene conversion/ PMS events and crossing-over led to the proposal that these processes were mechanistically linked (Kitani et al. 1962;Perkins 1962;Whitehouse 1963). MOLECULAR MODELS OF MEIOTIC RECOMBINATIONHolliday's classic model reconciled gene conversion, PMS, and crossing-over into a single mechanism with the key features of hybrid (heteroduplex) DNA formed via strand exchange, mismatch correction of hybrid DNA to yield gene conversion, and a four-way exchange junction that could be resolved to yield either crossover or noncrossover duplex products (Holliday...

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Section: The Str/btr Ensembles Are Master Regulators Of Meiotic Jointsupporting

confidence: 79%

Meiotic Recombination: The Essence of Heredity

Hunter

2015

Cold Spring Harb Perspect Biol

694

869

View full text Add to dashboard Cite

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“…In Arabidopsis , redundant Blm paralogs prevent Class II crossovers, perhaps by promoting noncrossover repair, but are not required for Class I crossovers[31]. The C. elegans ortholog, HIM-6, does have a role in making Class I crossovers [32]; however, this occurs after normal crossover designation. This is not unlike Drosophila mei-9 mutants, where crossover designation is intact but crossover formation is impaired, resulting in the few crossovers that are made having a wild-type distribution [10] (Figure S1B).…”

Section: Resultsmentioning

confidence: 99%

Bloom Syndrome Helicase Promotes Meiotic Crossover Patterning and Homolog Disjunction

et al. 2017

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Summary In most sexually reproducing organisms, crossover formation between homologous chromosomes is necessary for proper chromosome disjunction during meiosis I. During meiotic recombination, a subset of programmed DNA double-strand breaks (DSBs) are repaired as crossovers, with the remainder becoming noncrossovers [1]. Whether a repair intermediate is designated to become a crossover is a highly-regulated decision that integrates several crossover patterning processes, both along chromosome arms (interference and the centromere effect) and between chromosomes (crossover assurance) [2]. Because the mechanisms that generate crossover patterning have remained elusive for over a century, it has been difficult to assess the relationship between crossover patterning and meiotic chromosome behavior. We show here that meiotic crossover patterning is lost in Drosophila melanogaster mutants that lack the Bloom syndrome helicase. In the absence of interference and the centromere effect, crossovers are distributed more uniformly along chromosomes. Crossovers even occur on the small chromosome 4, which normally never has meiotic crossovers [3]. Regulated distribution of crossovers between chromosome pairs is also lost, resulting in an elevated frequency of homologs that do not receive a crossover, which in turn leads to elevated nondisjunction.

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“…RMI-1 and HIM-6 (BLM) have been also shown to facilitate class I CO in C. elegans (46,47). Intriguingly, Arabidopsis rmi1-4, rmi1-5 and top3α-R640X single mutants show some univalents at metaphase I (about 1 for every 8 cells, Figure 1A and (16)), while they largely restore CO in zmms .…”

Section: Resultsmentioning

confidence: 99%

RMI1 and TOP3α limit meiotic CO formation through their C-terminal domains

et al. 2016

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At meiosis, hundreds of programmed DNA double-strand breaks (DSBs) form and are repaired by homologous recombination. From this large number of DSBs, only a subset yields crossovers (COs), with a minimum of one CO per chromosome pair. All DSBs must be repaired and every recombination intermediate must be resolved to avoid subsequent entanglement and chromosome breakage. The conserved BLM-TOP3α-RMI1 (BTR) complex acts on early and late meiotic recombination intermediates to both limit CO outcome and promote chromosome integrity. In Arabidopsis, the BLM homologues RECQ4A and RECQ4B act redundantly to prevent meiotic extra COs, but recombination intermediates are fully resolved in their absence. In contrast, TOP3α is needed for both processes. Here we show through the characterization of specific mutants that RMI1 is a major anti-CO factor, in addition to being essential to prevent chromosome breakage and entanglement. Further, our findings suggest a specific role of the C-terminal domains of RMI1 and TOP3α, that respectively contain an Oligo Binding domain (OB2) and ZINC finger motifs, in preventing extra-CO. We propose that these domains of TOP3α and RMI1 define a sub-domain of the BTR complex which is dispensable for the resolution of recombination intermediates but crucial to limit extra-COs.

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

Cited by 33 publications

References 56 publications

Meiotic Recombination: The Essence of Heredity

Meiotic Recombination: The Essence of Heredity

Bloom Syndrome Helicase Promotes Meiotic Crossover Patterning and Homolog Disjunction

RMI1 and TOP3α limit meiotic CO formation through their C-terminal domains

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