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

Published on Oct 1, 2016in Cell 31.40
· 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)
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)
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References52
Newest
Published on Jun 1, 2016in Seminars in Cell & Developmental Biology 6.14
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...
16 Citations Source Cite
Published on Feb 1, 2016in Genes & Development 9.46
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...
41 Citations Source Cite
Published on Feb 1, 2016in Nature 41.58
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...
63 Citations Source Cite
Published on Jan 2, 2016in Cell Cycle 3.30
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...
15 Citations Source Cite
Published on Nov 20, 2015in Science 41.06
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 ...
51 Citations Source Cite
Published on Oct 28, 2015in Cold Spring Harbor Perspectives in Biology 9.25
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...
157 Citations Source Cite
Published on Aug 15, 2015in Genes & Development 9.46
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...
16 Citations Source Cite
Published on Apr 1, 2015in Nature 41.58
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.
40 Citations Source Cite
Published on Jan 8, 2015in PLOS Genetics 5.54
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...
62 Citations Source Cite
Published on Nov 23, 2014in Annual Review of Genetics 9.59
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...
85 Citations Source Cite
Cited By64
Newest
Published on Aug 1, 2019in Journal of Cellular Physiology 3.92
Jun‐Jie Wang1
Estimated H-index: 1
(Life Sciences Institute),
Qiu-Yue Zhai1
Estimated H-index: 1
(Life Sciences Institute)
+ 6 AuthorsWei Shen (Life Sciences Institute)
Source Cite
Published on Jul 1, 2019in DNA Repair 4.46
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Published on Jun 25, 2019in Chromosoma 4.02
Source Cite
Published on May 1, 2019in Trends in Genetics 10.56
Mateusz Zelkowski (Cornell University), Mischa A. Olson2
Estimated H-index: 2
(Cornell University)
+ 1 AuthorsWojtek Pawlowski1
Estimated H-index: 1
(Cornell University)
Despite the universal importance of meiotic recombination for generating genetic diversity, numbers and distribution of recombination events along chromosomes vary among species, genotypes within species, and between sexes. Some interspecies differences stem from the diversity of genome size and composition among eukaryotes. Large-genome species, such as humans and most crops, display recombination landscapes that are different from those of small-genome yeasts. Chromatin patterns, including his...
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Published on Apr 1, 2019
Angelika Heissl2
Estimated H-index: 2
(Johannes Kepler University of Linz),
Andrea J. Betancourt15
Estimated H-index: 15
(University of Liverpool)
+ 5 AuthorsIrene Tiemann-Boege11
Estimated H-index: 11
(Johannes Kepler University of Linz)
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Published on Apr 1, 2019in Molecular Cell 14.25
Frantzeskos Papanikos2
Estimated H-index: 2
(TUD: Dresden University of Technology),
Julie A.J. Clément3
Estimated H-index: 3
(University of Montpellier)
+ 15 AuthorsAlexander Schleiffer36
Estimated H-index: 36
(Institute of Molecular Biotechnology)
Summary Orderly segregation of chromosomes during meiosis requires that crossovers form between homologous chromosomes by recombination. Programmed DNA double-strand breaks (DSBs) initiate meiotic recombination. We identify ANKRD31 as a key component of complexes of DSB-promoting proteins that assemble on meiotic chromosome axes. Genome-wide, ANKRD31 deficiency causes delayed recombination initiation. In addition, loss of ANKRD31 alters DSB distribution because of reduced selectivity for sites t...
1 Citations Source Cite
Published on Mar 22, 2019in Science 41.06
Anjali Gupta Hinch3
Estimated H-index: 3
(University of Oxford),
Gang Zhang1
Estimated H-index: 1
(University of Oxford)
+ 5 AuthorsPeter Donnelly91
Estimated H-index: 91
(University of Oxford)
INTRODUCTION In diploid organisms, the two chromosomes in each homologous pair act independently of each other during most cellular functions. An exception occurs in meiosis, in which the pair of chromosomes must first locate each other in the cell nucleus and then physically exchange genetic material through recombination and crossing over. This physical exchange is mechanistically essential for proper chromosomal segregation in meiosis. Along with mutation, it also shapes patterns of genetic v...
1 Citations Source Cite