Match!

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

Published on Oct 1, 2016in Cell36.22
· DOI :10.1016/j.cell.2016.09.035
Julian Lange12
Estimated H-index: 12
(MSK: Memorial Sloan Kettering Cancer Center),
Shintaro Yamada3
Estimated H-index: 3
(MSK: Memorial Sloan Kettering Cancer Center)
+ 6 AuthorsScott Keeney47
Estimated H-index: 47
(Cornell University)
Cite
Abstract
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.
  • References (52)
  • Citations (64)
Cite
References52
Newest
Published on Jun 1, 2016in Seminars in Cell & Developmental Biology5.46
Seoyoung Kim3
Estimated H-index: 3
(MSK: Memorial Sloan Kettering Cancer Center),
Shaun Peterson2
Estimated H-index: 2
(MSK: Memorial Sloan Kettering Cancer Center)
+ 1 AuthorsScott Keeney47
Estimated H-index: 47
(MSK: Memorial Sloan Kettering Cancer Center)
During meiosis, numerous DNA double-strand breaks (DSBs) are formed as part of the normal developmental program. This seemingly destructive behavior is necessary for successful meiosis, since repair of the DSBs through homologous recombination (HR) helps to produce physical links between the homologous chromosomes essential for correct chromosome segregation later in meiosis. However, DSB formation at such a massive scale also introduces opportunities to generate gross chromosomal rearrangements...
Published on Feb 1, 2016in Genes & Development8.99
Fatima Smagulova5
Estimated H-index: 5
(USU: Uniformed Services University of the Health Sciences),
Kevin Brick11
Estimated H-index: 11
(NIH: National Institutes of Health)
+ 2 AuthorsGalina V. Petukhova18
Estimated H-index: 18
(USU: Uniformed Services University of the Health Sciences)
Meiotic recombination is required for the segregation of homologous chromosomes and is essential for fertility. In most mammals, the DNA double-strand breaks (DSBs) that initiate meiotic recombination are directed to a subset of genomic loci (hot spots) by sequence-specific binding of the PRDM9 protein. Rapid evolution of the DNA-binding specificity of PRDM9 and gradual erosion of PRDM9-binding sites by gene conversion will alter the recombination landscape over time. To better understand the ev...
Published on Feb 1, 2016in Nature43.07
Benjamin Davies25
Estimated H-index: 25
,
Edouard Hatton2
Estimated H-index: 2
+ 15 AuthorsR Diaz4
Estimated H-index: 4
PRDM9 is a DNA-binding protein that controls the position of double-strand breaks in meiosis, and the gene that encodes it is responsible for hybrid infertility between closely related mouse species; this hybrid infertility is eliminated by introducing the zinc-finger domain sequence from the human version of the PRDM9 gene, a change which alters both the position of double-strand breaks and the symmetry of PRDM9 binding and suggests that PRDM9 may have a more general but transient role in the e...
Published on Jan 2, 2016in Cell Cycle3.26
Tim J. Cooper4
Estimated H-index: 4
(University of Sussex),
Valerie Garcia9
Estimated H-index: 9
,
Matthew J. Neale15
Estimated H-index: 15
(University of Sussex)
Meiosis is a specialized two-step cell division responsible for genome haploidization and the generation of genetic diversity during gametogenesis. An integral and distinctive feature of the meiotic program is the evolutionarily conserved initiation of homologous recombination (HR) by the developmentally programmed induction of DNA double-strand breaks (DSBs). The inherently dangerous but essential act of DSB formation is subject to multiple forms of stringent and self-corrective regulation that...
Published on Nov 20, 2015in Science41.04
Isabel Lam8
Estimated H-index: 8
(MSK: Memorial Sloan Kettering Cancer Center),
Scott Keeney47
Estimated H-index: 47
(MSK: Memorial Sloan Kettering Cancer Center)
The nonrandom distribution of meiotic recombination shapes heredity and genetic diversification. Theoretically, hotspots—favored sites of recombination initiation—either evolve rapidly toward extinction or are conserved, especially if they are chromosomal features under selective constraint, such as promoters. We tested these theories by comparing genome-wide recombination initiation maps from widely divergent Saccharomyces species. We find that hotspots frequently overlap with promoters in the ...
Published on Oct 28, 2015in Cold Spring Harbor Perspectives in Biology9.11
Neil Hunter30
Estimated H-index: 30
(HHMI: Howard Hughes Medical Institute)
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 recombinati...
Published on Aug 15, 2015in Genes & Development8.99
Esther de Boer1
Estimated H-index: 1
(MSK: Memorial Sloan Kettering Cancer Center),
Maria Jasin76
Estimated H-index: 76
(MSK: Memorial Sloan Kettering Cancer Center),
Scott Keeney47
Estimated H-index: 47
(MSK: Memorial Sloan Kettering Cancer Center)
Meiotic recombination initiated by programmed double-strand breaks (DSBs) yields two types of interhomolog recombination products, crossovers and noncrossovers, but what determines whether a DSB will yield a crossover or noncrossover is not understood. In this study, we analyzed the influence of sex and chromosomal location on mammalian recombination outcomes by constructing fine-scale recombination maps in both males and females at two mouse hot spots located in different regions of the same ch...
Published on Apr 1, 2015in Nature43.07
Valerie Garcia9
Estimated H-index: 9
,
Stephen Gray4
Estimated H-index: 4
+ 2 AuthorsMatthew J. Neale15
Estimated H-index: 15
Meiotic recombination is initiated by a fairly uniform distribution of hundreds of DNA double-strand breaks catalysed by the Spo11 protein; here, Tel1 (orthologue of human ATM) is shown to be required for the localized inhibition that prevents double-strand breaks from forming close to one another.
Published on Jan 8, 2015in PLOS Genetics5.22
Christopher L. Baker16
Estimated H-index: 16
,
Shimpei Kajita6
Estimated H-index: 6
(Okayama University)
+ 5 AuthorsKenneth Paigen15
Estimated H-index: 15
Meiotic recombination generates new genetic variation and assures the proper segregation of chromosomes in gametes. PRDM9, a zinc finger protein with histone methyltransferase activity, initiates meiotic recombination by binding DNA at recombination hotspots and directing the position of DNA double-strand breaks (DSB). The DSB repair mechanism suggests that hotspots should eventually self-destruct, yet genome-wide recombination levels remain constant, a conundrum known as the hotspot paradox. To...
Published on Nov 23, 2014in Annual Review of Genetics9.18
Scott Keeney47
Estimated H-index: 47
,
Julian Lange12
Estimated H-index: 12
,
Neeman Mohibullah4
Estimated H-index: 4
Recombination in meiosis is a fascinating case study for the coordination of chromosomal duplication, repair, and segregation with each other and with progression through a cell-division cycle. Meiotic recombination initiates with formation of developmentally programmed DNA double-strand breaks (DSBs) at many places across the genome. DSBs are important for successful meiosis but are also dangerous lesions that can mutate or kill, so cells ensure that DSBs are made only at the right times, place...
Cited By64
Newest
Published on Dec 1, 2019in Nature Communications11.88
Vijayalakshmi V. Subramanian5
Estimated H-index: 5
(NYU: New York University),
Xuan Zhu4
Estimated H-index: 4
(Amazon.com)
+ 5 AuthorsAndreas Hochwagen21
Estimated H-index: 21
(NYU: New York University)
Faithful meiotic chromosome inheritance and fertility rely on the stimulation of meiotic crossover recombination by potentially genotoxic DNA double-strand breaks (DSBs). To avoid excessive damage, feedback mechanisms down-regulate DSBs, likely in response to initiation of crossover repair. In Saccharomyces cerevisiae, this regulation requires the removal of the conserved DSB-promoting protein Hop1/HORMAD during chromosome synapsis. Here, we identify privileged end-adjacent regions (EARs) spanni...
Published on Dec 1, 2019in Nature Communications11.88
Ran Li2
Estimated H-index: 2
(University of Oxford),
Emmanuelle Bitoun11
Estimated H-index: 11
(University of Oxford)
+ 3 AuthorsSimon Myers40
Estimated H-index: 40
(University of Oxford)
During meiotic recombination, homologue-templated repair of programmed DNA double-strand breaks (DSBs) produces relatively few crossovers and many difficult-to-detect non-crossovers. By intercrossing two diverged mouse subspecies over five generations and deep-sequencing 119 offspring, we detect thousands of crossover and non-crossover events genome-wide with unprecedented power and spatial resolution. We find that both crossovers and non-crossovers are strongly depleted at DSB hotspots where th...
Published on Dec 1, 2019in Epigenetics & Chromatin4.18
Iyer Aditya Mahadevan (Jawaharlal Nehru Centre for Advanced Scientific Research), Satyakrishna Pentakota (UCPH: University of Copenhagen)+ 2 AuthorsManchanahalli R. Satyanarayana Rao23
Estimated H-index: 23
(Jawaharlal Nehru Centre for Advanced Scientific Research)
Background TH2B is a major histone variant that replaces about 80–85% of somatic H2B in mammalian spermatocytes and spermatids. The post-translational modifications (PTMs) on TH2B have been well characterised in spermatocytes and spermatids. However, the biological function(s) of these PTMs on TH2B have not been deciphered in great detail. In our attempt to decipher the unique function(s) of histone variant TH2B, we detected the modification in the N-terminal tail, Serine 11 phosphorylation on T...
Published on 2019in Nature Communications11.88
Kwan-Wood G. Lam5
Estimated H-index: 5
(NIH: National Institutes of Health),
Kevin Brick11
Estimated H-index: 11
(NIH: National Institutes of Health)
+ 2 AuthorsR. Daniel Camerini-Otero38
Estimated H-index: 38
(NIH: National Institutes of Health)
Meiosis is the specialized cell division during which parental genomes recombine to create genotypically unique gametes. Despite its importance, mammalian meiosis cannot be studied in vitro, greatly limiting mechanistic studies. In vivo, meiocytes progress asynchronously through meiosis and therefore the study of specific stages of meiosis is a challenge. Here, we describe a method for isolating pure sub-populations of nuclei that allows for detailed study of meiotic substages. Interrogating the...
Published on Sep 23, 2019in International Journal of Molecular Sciences4.18
Meiosis is an essential cell-division process for ensuring genetic diversity across generations. Meiotic recombination ensures the accuracy of genetic interchange between homolous chromosomes and segregation of parental alleles. Programmed DNA double-strand breaks (DSBs), catalyzed by the evolutionarily conserved topoisomerase VIA (a subunit of the archaeal type II DNA topoisomerase)-like enzyme Spo11 and several other factors, is a distinctive feature of meiotic recombination initiation. The me...
Published on Sep 10, 2019in bioRxiv
Catrina Spruce2
Estimated H-index: 2
,
S. Dlamini + 5 AuthorsChristopher L. Baker16
Estimated H-index: 16
Chromatin barriers prevent spurious interactions between regulatory elements and DNA-binding proteins. One such barrier, whose mechanism for overcoming is poorly understood, is access to recombination hotspots during meiosis. Here we show that the chromatin remodeler HELLS and DNA-binding protein PRDM9 function together to open chromatin at hotspots and provide access for the DNA double-strand break (DSB) machinery. Recombination hotspots are decorated by a unique combination of histone modifica...
Ipsita Agarwal1
Estimated H-index: 1
,
Molly Przeworski45
Estimated H-index: 45
The sources of human germline mutations are poorly understood. Part of the difficulty is that mutations occur very rarely, and so direct pedigree-based approaches remain limited in the numbers that they can examine. To address this problem, we consider the spectrum of low-frequency variants in a dataset (Genome Aggregation Database, gnomAD) of 13,860 human X chromosomes and autosomes. X-autosome differences are reflective of germline sex differences and have been used extensively to learn about ...
Published on 2019in Journal of Cell Biology8.89
Nathan M. Palmer1
Estimated H-index: 1
(Agency for Science, Technology and Research),
S. Zakiah A. Talib2
Estimated H-index: 2
(Agency for Science, Technology and Research)
+ 7 AuthorsSheena Wee8
Estimated H-index: 8
(Agency for Science, Technology and Research)
Meiosis generates four genetically distinct haploid gametes over the course of two reductional cell divisions. Meiotic divisions are characterized by the coordinated deposition and removal of various epigenetic marks. Here we propose that nuclear respiratory factor 1 (NRF1) regulates transcription of euchromatic histone methyltransferase 1 (EHMT1) to ensure normal patterns of H3K9 methylation during meiotic prophase I. We demonstrate that cyclin-dependent kinase (CDK2) can bind to the promoters ...
Published on Sep 1, 2019in Molecular Cell14.55
Yi Yin4
Estimated H-index: 4
(UW: University of Washington),
Yue Jiang1
Estimated H-index: 1
+ 7 AuthorsJay Shendure94
Estimated H-index: 94
Summary Conventional methods for single-cell genome sequencing are limited with respect to uniformity and throughput. Here, we describe sci-L3, a single-cell sequencing method that combines combinatorial indexing (sci-) and linear (L) amplification. The sci-L3 method adopts a 3-level (3) indexing scheme that minimizes amplification biases while enabling exponential gains in throughput. We demonstrate the generalizability of sci-L3 with proof-of-concept demonstrations of single-cell whole-genome ...
Published on Jul 1, 2019in DNA Repair3.71
Mridula Nambiar3
Estimated H-index: 3
(Fred Hutchinson Cancer Research Center),
Yu-Chien Chuang (Fred Hutchinson Cancer Research Center), Gerald R. Smith47
Estimated H-index: 47
(Fred Hutchinson Cancer Research Center)
Abstract During meiosis, homologous chromosomes of a diploid cell are replicated and, without a second replication, are segregated during two nuclear divisions to produce four haploid cells (including discarded polar bodies in females of many species). Proper segregation of chromosomes at the first division requires in most species that homologous chromosomes be physically connected. Tension generated by connected chromosomes moving to opposite sides of the cell signals proper segregation. In th...
View next paperGenetic recombination is directed away from functional genomic elements in mice