A DNA topoisomerase VI–like complex initiates meiotic recombination

Vrielynck, Nathalie; Chambon, Aurélie; Vezon, Daniel; Pereira, Lucie; Chelysheva, Liudmila; Muyt, Arnaud De; Mézard, Christine; Mayer, Claudine; Grelon, Mathilde

doi:10.1126/science.aad5196

Cited by 214 publications

(250 citation statements)

References 48 publications

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“…The meiosisspecific RAD51 ortholog DMC1 is activated in glioblastoma and it contributes to proliferative potential and genotoxic stress recovery (44). In addition, during meiosis, interhomolog recombination is initiated by the type II topoisomerase-like activity of the SPO11-TOPVIBL complex, which generates a DNA doublestrand break in one participating chromatid (45)(46)(47)(48). Recent work in mice has demonstrated that the mammalian-specific gene Tex19.1 is required to promote normal levels of these meiotic recombination-initiating events (49).…”

Section: Activation Of Meiotic Functions In Cancer Cellsmentioning

confidence: 99%

Meiosis-like Functions in Oncogenesis: A New View of Cancer

McFarlane

Wakeman

2017

Cancer Research

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Cancer cells have many abnormal characteristics enabling tumors to grow, spread, and avoid immunologic and therapeutic destruction. Central to this is the innate ability of populations of cancer cells to rapidly evolve. One feature of many cancers is that they activate genes that are normally associated with distinct developmental states, including germ cell–specific genes. This has historically led to the proposal that tumors take on embryonal characteristics, the so called embryonal theory of cancer. However, one group of germline genes, not directly associated with embryonic somatic tissue genesis, is the one that encodes the specific factors to drive the unique reductional chromosome segregation of meiosis I, which also results in chromosomal exchanges. Here, we propose that meiosis I–specific modulators of reductional segregation can contribute to oncogenic chromosome dynamics and that the embryonal theory for cancer cell growth/proliferation is overly simplistic, as meiotic factors are not a feature of most embryonic tissue development. We postulate that some meiotic chromosome-regulatory functions contribute to a soma-to-germline model for cancer, in which activation of germline (including meiosis) functions drive oncogenesis, and we extend this to propose that meiotic factors could be powerful sources of targets for therapeutics and biomonitoring in oncology. Cancer Res; 77(21); 5712–6. ©2017 AACR.

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Section: Activation Of Meiotic Functions In Cancer Cellsmentioning

confidence: 99%

Meiosis-like Functions in Oncogenesis: A New View of Cancer

McFarlane

Wakeman

2017

Cancer Research

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“…This specific recombination pathway is initiated by the formation of DNA double-strand breaks (DSBs) (de Massy 2013) that are generated by the SPO11/TOPOVIBL protein complex (Robert et al 2016;Vrielynck et al 2016) and repaired by homologous recombination Hunter 2015). DSB repair leads to reciprocal and nonreciprocal exchanges of genetic material between paternal and maternal chromosomes, called cross-overs and gene conversions, respectively.…”

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

In vivo binding of PRDM9 reveals interactions with noncanonical genomic sites

et al. 2017

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In mouse and human meiosis, DNA double-strand breaks (DSBs) initiate homologous recombination and occur at specific sites called hotspots. The localization of these sites is determined by the sequence-specific DNA binding domain of the PRDM9 histone methyl transferase. Here, we performed an extensive analysis of PRDM9 binding in mouse spermatocytes. Unexpectedly, we identified a noncanonical recruitment of PRDM9 to sites that lack recombination activity and the PRDM9 binding consensus motif. These sites include gene promoters, where PRDM9 is recruited in a DSB-dependent manner. Another subset reveals DSB-independent interactions between PRDM9 and genomic sites, such as the binding sites for the insulator protein CTCF. We propose that these DSB-independent sites result from interactions between hotspot-bound PRDM9 and genomic sequences located on the chromosome axis.

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“…AtSPO11-1 and AtSPO11-2, as subunits of a heterodimer, are essential for DSB formation whereas AtSPO11-3 is not required for DSB formation (10). Recently, an Arabidopsis homolog of the archaeal topo VIB subunit (MTOPVIB) was found to interact with the SPO11-1/2 heterodimer and participate in DSB formation (11).…”

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confidence: 99%

P31 ^comet , a member of the synaptonemal complex, participates in meiotic DSB formation in rice

Tang

Shen

et al. 2016

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

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The human mitotic arrest-deficient 2 (Mad2) binding protein p31 comet participates in the spindle checkpoint and coordinates cell cycle events in mitosis although its function in meiosis remains unknown in all organisms. Here, we reveal P31 comet as a synaptonemal complex (SC) protein in rice (Oryza sativa L.). In p31 comet , homologous pairing and synapsis are eliminated, leading to the homologous nondisjunction and complete sterility. The failure in loading of histone H2AX phosphorylation (γH2AX) in p31 comet , together with the suppressed chromosome fragmentation in rice completion of meiotic recombination 1 (com1) p31 comet and radiation sensitive 51c (rad51c) p31 comet double mutants, indicates that P31 comet plays an essential role in double-strand break (DSB) formation. Interestingly, the dynamic colocalization pattern between P31 comet and ZEP1 (a transverse filament protein of SC) by immunostaining, as well as the interaction between P31 comet and CENTRAL REGION COMPONENT 1 (CRC1) in yeast two-hybrid assays, suggests possible involvement of P31 comet in SC installation. Together, these data indicate that P31 comet plays a key role in DSB formation and SC installation, mainly through its cooperation with CRC1.uring meiosis, homologous recombination plays a crucial role in ensuring faithful and precise chromosome segregation, as well as in diversifying genetic information. Meiotic recombination is induced by the programmed formation of DNA double-strand breaks (DSBs), catalyzed by Spo11, a functional homolog of subunit A of an archaeal topoisomerase (TopoVIA) (1). In Saccharomyces cerevisiae, nine associated proteins, including meiotic recombination 11 (Mre11), radiation sensitive 50 (Rad50), X-ray sensitive 2 (Xrs2), superkiller 8 (Ski8), Rec102, Rec104, Rec114, meiosis-specific 4 (Mei4), and Mer2, are required for facilitating Spo11's catalytic reaction (2). In Schizosaccharomyces pombe, seven DSB formation-related proteins were identified (3). Rec6 has been recognized as an essential component for ensuring the meiotic DSB formation, and it forms a complex with Rec12 and Rec14, the orthologs of Spo11 and Ski8, respectively (4). Furthermore, the Mde2 protein, which lacks an ortholog in S. cerevisiae, is also required for DSB formation (5). Nevertheless, Rad50, Mre11, and Xrs2 orthologs are dispensable for DSB formation in S. pombe, as well as in mice and plants, but they are required for meiotic DSB processing (6). In mice, except for the conserved protein Spo11, Mei4 and Rec114 were also identified as key components involved in DSB formation (7). In addition, Mei1 was recognized as a recombination related factor, without an ortholog in S. cerevisiae or S. pombe (8). Recently, mouse TOPOVIBL protein was identified to form the complex with Spo11 and take part in meiotic DSB formation (9).In plants, the Arabidopsis AtSPO11-1, AtSPO11-2, and AtSPO11-3 share sequence similarity with other Spo11/topo VIA proteins. AtSPO11-1 and AtSPO11-2, as subunits of a heterodimer, are essential for DSB formation whereas A...

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A DNA topoisomerase VI–like complex initiates meiotic recombination

Cited by 214 publications

References 48 publications

Meiosis-like Functions in Oncogenesis: A New View of Cancer

Meiosis-like Functions in Oncogenesis: A New View of Cancer

In vivo binding of PRDM9 reveals interactions with noncanonical genomic sites

P31 ^comet , a member of the synaptonemal complex, participates in meiotic DSB formation in rice

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A DNA topoisomerase VI–like complex initiates meiotic recombination

Cited by 214 publications

References 48 publications

Meiosis-like Functions in Oncogenesis: A New View of Cancer

Meiosis-like Functions in Oncogenesis: A New View of Cancer

In vivo binding of PRDM9 reveals interactions with noncanonical genomic sites

P31 comet , a member of the synaptonemal complex, participates in meiotic DSB formation in rice

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P31 ^comet , a member of the synaptonemal complex, participates in meiotic DSB formation in rice