Top3-Rmi1 Dissolve Rad51-Mediated D Loops by a Topoisomerase-Based Mechanism

Fasching, Clare L.; Ćejka, Petr; Kowalczykowski, Stephen C.; Heyer, Wolf Dietrich

doi:10.1016/j.molcel.2015.01.022

Cited by 106 publications

(135 citation statements)

References 60 publications

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“…These complexes comprise RecQ helicases, Sgs1/BLM, their cognate type-I topoisomerases, Top3/TOPIIIa, and accessory factors Rmi1/RMI1 -RMI2. In isolation, Sgs1/ BLM can migrate HJs and unwind proteinfree D-loops (Karow et al 2000;van Brabant et al 2000;Bachrati et al 2006;Fasching et al 2015), but in combination with the single-strand passage activity of Top3 -Rmi1/TOPIIIa -RMI1 -RMI2, the STR/BTR complexes perform a unique re-action to dissociate dHJs into component duplexes. This convergent branch migration and decatenation reaction yields exclusively noncrossover products and has been termed dissolution to distinguish it from endonuclease-mediated resolution (Wu and Hickson 2003;Wu et al 2006;Bussen et al 2007;Singh et al 2008;Xu et al 2008;Bocquet et al 2014).…”

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

confidence: 99%

Meiotic Recombination: The Essence of Heredity

Hunter

2015

Cold Spring Harb Perspect Biol

673

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 Jointmentioning

confidence: 99%

Meiotic Recombination: The Essence of Heredity

Hunter

2015

Cold Spring Harb Perspect Biol

673

869

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“…While this article was under review, three independent studies also addressed the function of Top3 in DSB repair and meiosis (29)(30)(31). They revealed that in S. Cerevisiae Top3-Rmi1 acts with Sgs1 to channel JMs into CO and NCO pathways and prevent aberrant recombination intermediate accumulation.…”

Section: −9mentioning

confidence: 99%

Multiple mechanisms limit meiotic crossovers: TOP3α and two BLM homologs antagonize crossovers in parallel to FANCM

Séguéla-Arnaud

Crismani

Larchevêque

et al. 2015

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

144

241

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Meiotic crossovers (COs) have two important roles, shuffling genetic information and ensuring proper chromosome segregation. Despite their importance and a large excess of precursors (i.e., DNA doublestrand breaks, DSBs), the number of COs is tightly regulated, typically one to three per chromosome pair. The mechanisms ensuring that most DSBs are repaired as non-COs and the evolutionary forces imposing this constraint are poorly understood. Here we identified Topoisomerase3α (TOP3α) and the RECQ4 helicases-the Arabidopsis slow growth suppressor 1 (Sgs1)/Bloom syndrome protein (BLM) homologs-as major barriers to meiotic CO formation. First, the characterization of a specific TOP3α mutant allele revealed that, in addition to its role in DNA repair, this topoisomerase antagonizes CO formation. Further, we found that RECQ4A and RECQ4B constitute the strongest meiotic anti-CO activity identified to date, their concomitant depletion leading to a sixfold increase in CO frequency. In both top3α and recq4ab mutants, DSB number is unaffected, and extra COs arise from a normally minor pathway. Finally, both TOP3α and RECQ4A/B act independently of the previously identified anti-CO Fanconi anemia of complementation group M (FANCM) helicase. This finding shows that several parallel pathways actively limit CO formation and suggests that the RECQA/B and FANCM helicases prevent COs by processing different substrates. Despite a ninefold increase in CO frequency, chromosome segregation was unaffected. This finding supports the idea that CO number is restricted not because of mechanical constraints but likely because of the long-term costs of recombination. Furthermore, this work demonstrates how manipulating a few genes holds great promise for increasing recombination frequency in plant-breeding programs.eiotic homologous recombination is initiated by the formation of DNA double-strand breaks (DSBs). DSBs are resected to form 3′ ssDNA overhangs which invade the intact homologous chromosome, producing DNA joint molecules (JMs). These JMs can be differentially processed to produce crossovers (COs) or non-COs (NCOs). In Arabidopsis thaliana, mammals, and budding yeast, two pathways of CO formation exist. The major pathway depends on the ZMM proteins (for Zip1-4, Msh4/5, and Mer3) in addition to MutL homolog 1 (MLH1) and MuL homolog 3 (MLH3) and produces interfering COs, so that one CO prevents the formation of another nearby (1). The second, pathway, producing noninterfering COs, depends on structure-specific endonucleases including MUS81 (1). These pro-CO pathways compete with anti-CO pathways, resulting in a minor portion of DSBs becoming COs; for instance, it is estimated that COs represent only 10% and 5% of DSBs in mouse and in Arabidopsis, respectively (2). Three helicases with meiotic anti-CO activities have been identified in different species: the Bloom syndrome (BLM) homolog, small growth suppressor 1 (Sgs1) in Saccharomyces cerevisiae (3, 4); regulator of telomere elongation helicase1 (RTEL-1) in Caenorhabditis elegans (5)...

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“…BLM (van Brabant et al 2000;Bachrati et al 2006) and Sgs1 (Fasching et al 2015) have also been shown to dissociate protein-free D-loops, providing the potential for a second way these enzymes may act as antirecombinases and/or enforce a noncrossover outcome by dissociating D-loops.…”

Section: Reversibility Of Extended D-loops: a Step In Sdsa And A Mechmentioning

confidence: 99%

Regulation of Recombination and Genomic Maintenance

Heyer

2015

Cold Spring Harb Perspect Biol

Self Cite

104

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Recombination is a central process to stably maintain and transmit a genome through somatic cell divisions and to new generations. Hence, recombination needs to be coordinated with other events occurring on the DNA template, such as DNA replication, transcription, and the specialized chromosomal functions at centromeres and telomeres. Moreover, regulation with respect to the cell-cycle stage is required as much as spatiotemporal coordination within the nuclear volume. These regulatory mechanisms impinge on the DNA substrate through modifications of the chromatin and directly on recombination proteins through a myriad of posttranslational modifications (PTMs) and additional mechanisms. Although recombination is primarily appreciated to maintain genomic stability, the process also contributes to gross chromosomal arrangements and copy-number changes. Hence, the recombination process itself requires quality control to ensure high fidelity and avoid genomic instability. Evidently, recombination and its regulatory processes have significant impact on human disease, specifically cancer and, possibly, neurodegenerative diseases.

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Top3-Rmi1 Dissolve Rad51-Mediated D Loops by a Topoisomerase-Based Mechanism

Cited by 106 publications

References 60 publications

Meiotic Recombination: The Essence of Heredity

Meiotic Recombination: The Essence of Heredity

Multiple mechanisms limit meiotic crossovers: TOP3α and two BLM homologs antagonize crossovers in parallel to FANCM

Regulation of Recombination and Genomic Maintenance

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