Mechanisms of germ line genome instability

Kim, Seo Young; Peterson, Shaun; Jasin, Maria; Keeney, Scott

doi:10.1016/j.semcdb.2016.02.019

Cited by 54 publications

(56 citation statements)

References 159 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Such non-allelic homologous recombination (NAHR) can lead to deleterious deletions, duplications, and other alterations. Indeed, NAHR-mediated chromosomal rearrangements in the germline are the cause of numerous developmental disorders in humans 3 , 59-61 . In budding yeast, DSB formation tends to be repressed within repetitive DNA genome-wide, 4 , 62 perhaps as a mechanism to protect against NAHR.…”

Section: Resultsmentioning

confidence: 99%

“…The non-random distribution of DSBs governs the evolution and diversity of eukaryotic genomes. Furthermore, failure to properly form and repair meiotic DSBs results in gametes with chromosome structure alterations or aneuploidy, which can lead to developmental disorders 2 , 3 . An important challenge has been to understand the complex interplay of multiple factors that shape this DSB landscape over size scales ranging from single nucleotides to whole chromosomes 4–6 …”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Genomic and chromatin features shaping meiotic double-strand break formation and repair in mice

et al. 2017

Self Cite

View full text Add to dashboard Cite

The SPO11-generated DNA double-strand breaks (DSBs) that initiate meiotic recombination occur non-randomly across genomes, but mechanisms shaping their distribution and repair remain incompletely understood. Here, we expand on recent studies of nucleotide-resolution DSB maps in mouse spermatocytes. We find that trimethylation of histone H3 lysine 36 around DSB hotspots is highly correlated, both spatially and quantitatively, with trimethylation of H3 lysine 4, consistent with coordinated formation and action of both PRDM9-dependent histone modifications. In contrast, the DSB-responsive kinase ATM contributes independently of PRDM9 to controlling hotspot activity, and combined action of ATM and PRDM9 can explain nearly two-thirds of the variation in DSB frequency between hotspots. DSBs were modestly underrepresented in most repetitive sequences such as segmental duplications and transposons. Nonetheless, numerous DSBs form within repetitive sequences in each meiosis and some classes of repeats are preferentially targeted. Implications of these findings are discussed for evolution of PRDM9 and its role in hybrid strain sterility in mice. Finally, we document the relationship between mouse strain-specific DNA sequence variants within PRDM9 recognition motifs and attendant differences in recombination outcomes. Our results provide further insights into the complex web of factors that influence meiotic recombination patterns.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genomic and chromatin features shaping meiotic double-strand break formation and repair in mice

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…Unlike DSB repair in most mitotic cells, DSB repair in meiotic cells involves the repair of programmed DSBs, typically using the homolog as a repair template, and with crossing over as a critical outcome [27, 28]. More than 100 DSBs are purposely introduced into the genome during meiosis by the SPO11-TOPOVIBL transesterase [29].…”

Section: Homologous Recombination: Dsb Repair and Gene Targetingmentioning

confidence: 99%

The democratization of gene editing: Insights from site-specific cleavage and double-strand break repair

2016

Self Cite

View full text Add to dashboard Cite

DNA double-strand breaks (DSBs) are dangerous lesions that if not properly repaired can lead to genomic change or cell death. Organisms have developed several pathways and have many factors devoted to repairing DSBs, which broadly occur by homologous recombination that relies on an identical or homologous sequence to template repair, or nonhomologous end-joining. Much of our understanding of these repair mechanisms has come from the study of induced DNA cleavage by site-specific endonucleases. In addition to their biological role, these cellular pathways can be co-opted for gene editing to study gene function or for gene therapy or other applications. While the first gene editing experiments were done more than 20 years ago, the recent discovery of RNA-guided endonucleases has simplified approaches developed over the years to make gene editing an approach that is available to the entire biomedical research community. Here, we review DSB repair mechanisms and site-specific cleavage systems that have provided insight into these mechanisms and led to the current gene editing revolution.

show abstract

“…The DSBs that initiate recombination are distributed nonrandomly in most species (reviewed in Baudat et al, 2013). The shape of this “DSB landscape” governs inheritance and genome evolution but also influences the risk of mutations and genome rearrangements (Kim et al, 2016). The factors shaping this landscape remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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

Lange

Yamada

Tischfield

et al. 2016

Cell

Self Cite

250

523

View full text Add to dashboard Cite

SUMMARY Heritability and genome stability are shaped by meiotic recombination, which is initiated via hundreds of DNA double-strand breaks (DSBs). The distribution of DSBs throughout the genome is not random, but mechanisms molding this landscape remain poorly understood. Here we exploit genome-wide maps of mouse DSBs at unprecedented nucleotide resolution to uncover previously invisible spatial features of recombination. At fine scale, we reveal a stereotyped hotspot structure—DSBs occur within narrow zones between methylated nucleosomes—and identify relationships between SPO11, chromatin, and the histone methyltransferase PRDM9. At large scale, DSB formation is suppressed on non-homologous portions of the sex chromosomes via the DSB-responsive kinase ATM, which also shapes the autosomal DSB landscape at multiple size scales. We also provide a genome-wide analysis of exonucleolytic DSB resection lengths and elucidate spatial relationships between DSBs and recombination products. Our results paint a comprehensive picture of features governing successive steps in mammalian meiotic recombination.

show abstract

Mechanisms of germ line genome instability

Cited by 54 publications

References 159 publications

Genomic and chromatin features shaping meiotic double-strand break formation and repair in mice

Genomic and chromatin features shaping meiotic double-strand break formation and repair in mice

The democratization of gene editing: Insights from site-specific cleavage and double-strand break repair

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

Contact Info

Product

Resources

About