Mechanism and Regulation of Meiotic Recombination Initiation

Lam, Isabel; Keeney, Scott

doi:10.1101/cshperspect.a016634

Cited by 394 publications

(474 citation statements)

References 236 publications

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“…There were no alterations in the pH2AX staining pattern in the E2F1 −/− ‐testis at P40 compared with E2F1 +/+ , which indicated that increased DNA damage was not the source of the spermatocyte apoptosis. In addition, this shows that the initial meiotic DSB formation occurred normally, as impaired DSB formation commonly leads to a decreased pH2AX staining in the spermatocytes (Hoja et al ., 2004; Lam & Keeney, 2014). This suggested that despite having high E2F1 expression levels in the cell types undergoing meiotic DSB formation, E2f1 did not contribute to this process.…”

Section: Discussionmentioning

confidence: 99%

E2F1 controls germ cell apoptosis during the first wave of spermatogenesis

et al. 2015

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SummaryCell cycle control during spermatogenesis is a highly complex process owing to the control of the mitotic expansion of the spermatogonial cell population and following meiosis, induction of DNA breaks during meiosis and the high levels of physiological germ‐cell apoptosis. We set out to study how E2F1, a key controller of cell cycle, apoptosis, and DNA damage responses, functions in the developing and adult testis. We first analyzed the expression pattern of E2f1 during post‐natal testis development using RNA in situ hybridization, which showed a differential expression pattern of E2f1 in the adult and juvenile mouse testes. To study the function of E2f1, we took advantage of the E2F1−/− mouse line, which was back‐crossed to C57Bl/6J genetic background. E2f1 loss led to a severe progressive testicular atrophy beginning at the age of 20 days. Spermatogonial apoptosis during the first wave of spermatogenesis was decreased. However, already in the first wave of spermatogenesis an extensive apoptosis of spermatocytes was observed. In the adult E2F1−/− testes, the atrophy due to loss of spermatocytes was further exacerbated by loss of spermatogonial stem cells. Surprisingly, only subtle changes in global gene expression array profiling were observed in E2F1−/− testis at PND20. To dissect the changes in each testicular cell type, an additional comparative analysis of the array data was performed making use of previously published data on transcriptomes of the individual testicular cell types. Taken together, our data indicate that E2F1 has a differential role during first wave of spermatogenesis and in the adult testis, which emphasizes the complex nature of cell cycle control in the developing testis.

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Section: Discussionmentioning

confidence: 99%

E2F1 controls germ cell apoptosis during the first wave of spermatogenesis

et al. 2015

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“…1) (see Mehta and Haber 2014). DSBR in meiotic recombination is initiated by the introduction of a large number of programmed DSBs catalyzed by the ScSpo11 protein (see Keeney et al 1997;Lam and Keeney 2015). In mouse and human cells, these programmed DSBs number in the several hundred (Kolas et al 2005;Lenzi et al 2005).…”

Section: Homologous Recombinationmentioning

confidence: 99%

Mismatch Repair during Homologous and Homeologous Recombination

Spies

Fishel

2015

Cold Spring Harb Perspect Biol

148

150

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Homologous recombination (HR) and mismatch repair (MMR) are inextricably linked. HR pairs homologous chromosomes before meiosis I and is ultimately responsible for generating genetic diversity during sexual reproduction. HR is initiated in meiosis by numerous programmed DNA double-strand breaks (DSBs; several hundred in mammals). A characteristic feature of HR is the exchange of DNA strands, which results in the formation of heteroduplex DNA. Mismatched nucleotides arise in heteroduplex DNA because the participating parental chromosomes contain nonidentical sequences. These mismatched nucleotides may be processed by MMR, resulting in nonreciprocal exchange of genetic information (gene conversion). MMR and HR also play prominent roles in mitotic cells during genome duplication; MMR rectifies polymerase misincorporation errors, whereas HR contributes to replication fork maintenance, as well as the repair of spontaneous DSBs and genotoxic lesions that affect both DNA strands. MMR suppresses HR when the heteroduplex DNA contains excessive mismatched nucleotides, termed homeologous recombination. The regulation of homeologous recombination by MMR ensures the accuracy of DSB repair and significantly contributes to species barriers during sexual reproduction. This review discusses the history, genetics, biochemistry, biophysics, and the current state of studies on the role of MMR in homologous and homeologous recombination from bacteria to humans.

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“…They arise during replication fork collapse or exposure to ionizing radiation, reactive oxygen species (ROS), or genotoxic chemicals (Sutherland et al, 2000;Costanzo et al, 2001;Pommier et al, 2003;Mahaney et al, 2009). DSBs are also enzymatically generated intermediates in meiotic recombination, V(D)J, and class switch recombination as well as yeast mating-type switching (Gapud & Sleckman, 2011;Haber, 2012;Xu et al, 2012;Lam & Keeney, 2015). Double-strand breaks can be repaired by different pathways.…”

Section: Introductionmentioning

confidence: 99%

Structural mechanism of ATP‐dependent DNA binding and DNA end bridging by eukaryotic Rad50

et al. 2016

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The Mre11-Rad50-Nbs1 (MRN) complex is a central factor in the repair of DNA double-strand breaks (DSBs). The ATP-dependent mechanisms of how MRN detects and endonucleolytically processes DNA ends for the repair by microhomology-mediated end-joining or further resection in homologous recombination are still unclear. Here, we report the crystal structures of the ATPcSbound dimer of the Rad50 NBD (nucleotide-binding domain) from the thermophilic eukaryote Chaetomium thermophilum (Ct) in complex with either DNA or CtMre11 RBD (Rad50-binding domain)along with small-angle X-ray scattering and cross-linking studies. The structure and DNA binding motifs were validated by DNA binding experiments in vitro and mutational analyses in Saccharomyces cerevisiae in vivo. Our analyses provide a structural framework for the architecture of the eukaryotic Mre11-Rad50 complex. They show that a Rad50 dimer binds approximately 18 base pairs of DNA along the dimer interface in an ATP-dependent fashion or bridges two DNA ends with a preference for 3 0 overhangs. Finally, our results may provide a general framework for the interaction of ABC ATPase domains of the Rad50/SMC/RecN protein family with DNA.

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Mechanism and Regulation of Meiotic Recombination Initiation

Cited by 394 publications

References 236 publications

E2F1 controls germ cell apoptosis during the first wave of spermatogenesis

E2F1 controls germ cell apoptosis during the first wave of spermatogenesis

Mismatch Repair during Homologous and Homeologous Recombination

Structural mechanism of ATP‐dependent DNA binding and DNA end bridging by eukaryotic Rad50

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