The Landscape of Mouse Meiotic Double-Strand Break Formation, Processing, and Repair

Lange, Julian; Yamada, Shintaro; Tischfield, Sam E.; Pan, Jing; Kim, Seo Young; Zhu, Xuan; Socci, Nicholas D.; Jasin, Maria; Keeney, Scott

doi:10.1016/j.cell.2016.09.035

Cited by 252 publications

(557 citation statements)

References 54 publications

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“…We conclude that the influence of local chromatin structure on hotspot position and shape is largely unaffected by tel1Δ and that the increase in Spo11-oligo levels is not principally from DSBs in regions that were previously inaccessible to Spo11. Interestingly, these findings contrast with those in mouse, where absence of ATM caused more hotspots to become detectable and caused hotspots to become wider (Lange et al 2016) (see Discussion).…”

Section: Altered Spo11-oligo Sizes In Tel1 Mutantscontrasting

confidence: 53%

“…Unlike in tel1Δ yeast, Atm −/− mouse spermatocytes display an increase in the number of SPO11-oligo hotspots called at a given threshold over the genome average; weaker hotspots show a disproportionate increase in strength; hotspots across relatively large (up to ∼10-15 Mb) regions display correlated behavior; and the magnitude of increase in hotspot heat is negatively correlated with local SPO11-oligo density in wild type (Lange et al 2016). These findings all point to ATM-dependent DSB inhibition working over relatively large (Mb-scale) domains, with this suppression having a substantial effect on the overall DSB landscape.…”

Section: Tel1 Shapes the Dsb Landscapementioning

confidence: 99%

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Numerical and spatial patterning of yeast meiotic DNA breaks by Tel1

2016

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The Spo11-generated double-strand breaks (DSBs) that initiate meiotic recombination are dangerous lesions that can disrupt genome integrity, so meiotic cells regulate their number, timing, and distribution. Mechanisms of this regulation remain poorly understood. Here, we use Spo11-oligonucleotide complexes, a byproduct of DSB formation, to reveal aspects of the contribution of the Saccharomyces cerevisiae DNA damage-responsive kinase Tel1 (ortholog of mammalian ATM). A tel1Δ mutant has globally increased amounts of Spo11-oligonucleotide complexes and altered Spo11-oligonucleotide lengths, consistent with conserved roles for Tel1 in control of DSB number and processing. A kinase-dead tel1 mutation similarly increases Spo11-oligonucleotide levels but mutating known Tel1 phosphotargets on Hop1 and Rec114 does not, implicating Tel1 kinase activity and clarifying roles of Tel1 phosphorylation substrates. Deep sequencing of Spo11 oligonucleotides demonstrates that Tel1 shapes the genome-wide DSB landscape in unexpected ways. Early in meiosis, Tel1 absence causes widespread changes in DSB distributions across large chromosomal domains. Many of these changes are erased as meiosis proceeds, however, illustrating homeostatic behavior of DSB regulatory systems. We further find that effects of Tel1 are distinct but partially overlapping with previously described contributions of the recombination regulator Cst9 (also known as Zip3). Finally, we provide evidence indicating that Tel1-dependent DSB interference influences the population-average DSB landscape but also demonstrate that locally inhibitory effects of an artificial hotspot insertion can be both Tel1-independent and chromosomal context-dependent. Our findings delineate Tel1 roles in regulating number and location of DSBs and illuminate the complex interplay between Tel1 and other pathways for DSB control.

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Section: Altered Spo11-oligo Sizes In Tel1 Mutantscontrasting

confidence: 53%

Section: Tel1 Shapes the Dsb Landscapementioning

confidence: 99%

Numerical and spatial patterning of yeast meiotic DNA breaks by Tel1

2016

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“…This striking difference implies that human gametes and embryos employ a different DNA damage response system, perhaps reflecting the evolutionary importance of maintaining germline genome integrity 32 . If, as seems likely, gametes and zygotes endure an increased number of DSBs during meiotic recombination and segregation, an efficient genome repair capacity would be critical 33 and unique zygotic DNA repair machinery might rely entirely on maternal oocyte factors deposited and stored during maturation since zygotes are transcriptionally silent. Recent studies suggest that oocytes might employ an ataxia-telangiectasia mutated (ATM)-mediated DNA damage signalling (DDS) pathway that regulates repair of DSBs via a homologous recombination mechanism 34 .…”

Section: Discussionmentioning

confidence: 99%

Correction of a pathogenic gene mutation in human embryos

Martí-Gutiérrez

Park

et al. 2017

Nature

797

540

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More than 10,000 monogenic inherited disorders have been identified, affecting millions of people worldwide. Among these are autosomal dominant mutations, where inheritance of a single copy of a defective gene can result in clinical symptoms. Genes in which dominant mutations manifest as late-onset adult disorders include BRCA1 and BRCA2, which are associated with a high risk of breast and ovarian cancers 1 , and MYBPC3, mutation of which causes hypertrophic cardiomyopathy (HCM) 2 . Because of their delayed manifestation, these mutations escape natural selection and are often transmitted to the next generation. Consequently, the frequency of some of these founder mutations in particular human populations is very high. For example, the MYBPC3 mutation is found at frequencies ranging from 2% to 8% 3 in major Indian populations, and the estimated frequency of both BRCA1 and BRCA2 mutations among Ashkenazi Jews exceeds 2% 4 .HCM is a myocardial disease characterized by left ventricular hypertrophy, myofibrillar disarray and myocardial stiffness; it has an estimated prevalence of 1:500 in adults 5 and manifests clinically with heart failure. HCM is the commonest cause of sudden death in otherwise healthy young athletes. HCM, while not a uniformly fatal condition, has a tremendous impact on the lives of individuals, including physiological (heart failure and arrhythmias), psychological (limited activity and fear of sudden death), and genealogical concerns. MYBPC3 mutations account for approximately 40% of all genetic defects causing HCM and are also responsible for a large fraction of other inherited cardiomyopathies, including dilated cardiomyopathy and left ventricular non-compaction 6 . MYBPC3 encodes the thick filament-associated cardiac myosin-binding protein C (cMyBP-C), a signalling node in cardiac myocytes that contributes to the maintenance of sarcomeric structure and regulation of both contraction and relaxation 2 .Current treatment options for HCM provide mostly symptomatic relief without addressing the genetic cause of the disease. Thus, the development of novel strategies to prevent germline transmission of founder mutations is desirable. One approach for preventing second-generation transmission is preimplantation genetic diagnosis (PGD) followed by selection of non-mutant embryos for transfer in the context of an in vitro fertilization (IVF) cycle. When only one parent carries a heterozygous mutation, 50% of the embryos should be mutationfree and available for transfer, while the remaining carrier embryos are discarded. Gene correction would rescue mutant embryos, increase the number of embryos available for transfer and ultimately improve pregnancy rates.Recent developments in precise genome-editing techniques and their successful applications in animal models have provided an option for correcting human germline mutations. In particular, CRISPR-Cas9 is a versatile tool for recognizing specific genomic sequences and inducing DSBs 7-10 . DSBs are then resolved by endogenous DNA repair mechanisms, prefer...

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“…Meiosis in prophase I involves a series of orchestrated and programmed biochemical events including generation of DNA DSBs, synapsing of the homologous chromosomes, meiotic sex chromosome inactivation and repair of DNA DSBs 15, 16. Meiotic recombination starts with the programmed formation of a DNA DSB, which is catalysed by the meiotic topoisomerase‐like protein SPO11 38, 39, 40.…”

Section: Discussionmentioning

confidence: 99%

Ablation of Ggnbp2 impairs meiotic DNA double‐strand break repair during spermatogenesis in mice

Guo

Liu

et al. 2018

J Cellular Molecular Medi

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Gametogenetin (GGN) binding protein 2 (GGNBP2) is a zinc finger protein expressed abundantly in spermatocytes and spermatids. We previously discovered that Ggnbp2 resection caused metamorphotic defects during spermatid differentiation and resulted in an absence of mature spermatozoa in mice. However, whether GGNBP2 affects meiotic progression of spermatocytes remains to be established. In this study, flow cytometric analyses showed a decrease in haploid, while an increase in tetraploid spermatogenic cells in both 30‐ and 60‐day‐old Ggnbp2 knockout testes. In spread spermatocyte nuclei, Ggnbp2 loss increased DNA double‐strand breaks (DSB), compromised DSB repair and reduced crossovers. Further investigations demonstrated that GGNBP2 co‐immunoprecipitated with a testis‐enriched protein GGN1. Immunofluorescent staining revealed that both GGNBP2 and GGN1 had the same subcellular localizations in spermatocyte, spermatid and spermatozoa. Ggnbp2 loss suppressed Ggn expression and nuclear accumulation. Furthermore, deletion of either Ggnbp2 or Ggn in GC‐2spd cells inhibited their differentiation into haploid cells in vitro. Overexpression of Ggnbp2 in Ggnbp2 null but not in Ggn null GC‐2spd cells partially rescued the defect coinciding with a restoration of Ggn expression. Together, these data suggest that GGNBP2, likely mediated by its interaction with GGN1, plays a role in DSB repair during meiotic progression of spermatocytes.

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The Landscape of Mouse Meiotic Double-Strand Break Formation, Processing, and Repair

Cited by 252 publications

References 54 publications

Numerical and spatial patterning of yeast meiotic DNA breaks by Tel1

Numerical and spatial patterning of yeast meiotic DNA breaks by Tel1

Correction of a pathogenic gene mutation in human embryos

Ablation of Ggnbp2 impairs meiotic DNA double‐strand break repair during spermatogenesis in mice

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