scholarly journals PRDM9 activity depends on HELLS and promotes local 5-hydroxymethylcytosine enrichment

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Yukiko Imai ◽  
Mathilde Biot ◽  
Julie AJ Clément ◽  
Mariko Teragaki ◽  
Serge Urbach ◽  
...  
Keyword(s):  
Binding Sites ◽  
Male Meiosis ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Chromatin Remodelers ◽  
Strand Breaks ◽  
Complex Regulation ◽  
Genomic Locations ◽  
Functional Analyses ◽  
Deficient Mice

Meiotic recombination starts with the formation of DNA double-strand breaks (DSBs) at specific genomic locations that correspond to PRDM9-binding sites. The molecular steps occurring from PRDM9 binding to DSB formation are unknown. Using proteomic approaches to find PRDM9 partners, we identified HELLS, a member of the SNF2-like family of chromatin remodelers. Upon functional analyses during mouse male meiosis, we demonstrated that HELLS is required for PRDM9 binding and DSB activity at PRDM9 sites. However, HELLS is not required for DSB activity at PRDM9-independent sites. HELLS is also essential for 5-hydroxymethylcytosine (5hmC) enrichment at PRDM9 sites. Analyses of 5hmC in mice deficient for SPO11, which catalyzes DSB formation, and in PRDM9 methyltransferase deficient mice reveal that 5hmC is triggered at DSB-prone sites upon PRDM9 binding and histone modification, but independent of DSB activity. These findings highlight the complex regulation of the chromatin and epigenetic environments at PRDM9-specified hotspots.

scholarly journals Four-pronged negative feedback of DSB machinery in meiotic DNA-break control in mice

2021 ◽  
Author(s):  
Ihsan Dereli ◽  
Marcello Stanzione ◽  
Fabrizio Olmeda ◽  
Frantzeskos Papanikos ◽  
Marek Baumann ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Protein Complexes ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Homologous Chromosomes ◽  
Damage Response ◽  
Auxiliary Protein ◽  
Genomic Locations ◽  
Spatiotemporal Control

Abstract In most taxa, halving of chromosome numbers during meiosis requires that homologous chromosomes (homologues) pair and form crossovers. Crossovers emerge from the recombination-mediated repair of programmed DNA double-strand breaks (DSBs). DSBs are generated by SPO11, whose activity requires auxiliary protein complexes, called pre-DSB recombinosomes. To elucidate the spatiotemporal control of the DSB machinery, we focused on an essential SPO11 auxiliary protein, IHO1, which serves as the main anchor for pre-DSB recombinosomes on chromosome cores, called axes. We discovered that DSBs restrict the DSB machinery by at least four distinct pathways in mice. Firstly, by activating the DNA damage response (DDR) kinase ATM, DSBs restrict pre-DSB recombinosome numbers without affecting IHO1. Secondly, in their vicinity, DSBs trigger IHO1 depletion mainly by another DDR kinase, ATR. Thirdly, DSBs enable homologue synapsis, which promotes the depletion of IHO1 and pre-DSB recombinosomes from synapsed axes. Finally, DSBs and three DDR kinases, ATM, ATR and PRKDC, enable stage-specific depletion of IHO1 from all axes. We hypothesize that these four negative feedback pathways protect genome integrity by ensuring that DSBs form without excess, are well-distributed, and are restricted to genomic locations and prophase stages where DSBs are functional for promoting homologue pairing and crossover formation.

scholarly journals Genetic Interactions of Histone Modification Machinery Set1 and PAF1C with the Recombination Complex Rec114-Mer2-Mei4 in the Formation of Meiotic DNA Double-Strand Breaks

2020 ◽  
Vol 21 (8) ◽  
pp. 2679
Author(s):  
Ying Zhang ◽  
Takuya Suzuki ◽  
Ke Li ◽  
Santosh K. Gothwal ◽  
Miki Shinohara ◽  
...  
Keyword(s):  
Histone Modification ◽  
Genetic Interaction ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
H3k4 Methylation ◽  
Yeast Saccharomyces Cerevisiae ◽  
Strand Breaks ◽  
Histone H3k4 ◽  
Genomic Locations ◽  
Chromosome Axis

Homologous recombination is essential for chromosome segregation during meiosis I. Meiotic recombination is initiated by the introduction of double-strand breaks (DSBs) at specific genomic locations called hotspots, which are catalyzed by Spo11 and its partners. DSB hotspots during meiosis are marked with Set1-mediated histone H3K4 methylation. The Spo11 partner complex, Rec114-Mer2-Mei4, essential for the DSB formation, localizes to the chromosome axes. For efficient DSB formation, a hotspot with histone H3K4 methylation on the chromatin loops is tethered to the chromosome axis through the H3K4 methylation reader protein, Spp1, on the axes, which interacts with Mer2. In this study, we found genetic interaction of mutants in a histone modification protein complex called PAF1C with the REC114 and MER2 in the DSB formation in budding yeast Saccharomyces cerevisiae. Namely, the paf1c mutations rtf1 and cdc73 showed synthetic defects in meiotic DSB formation only when combined with a wild-type-like tagged allele of either the REC114 or MER2. The synthetic defect of the tagged REC114 allele in the DSB formation was seen also with the set1, but not with spp1 deletion. These results suggest a novel role of histone modification machinery in DSB formation during meiosis, which is independent of Spp1-mediated loop-axis tethering.

scholarly journals Genome-Wide Redistribution of Meiotic Double-Strand Breaks in Saccharomyces cerevisiae

2006 ◽  
Vol 27 (5) ◽  
pp. 1868-1880 ◽  
Author(s):  
Nicolas Robine ◽  
Norio Uematsu ◽  
Franck Amiot ◽  
Xavier Gidrol ◽  
Emmanuel Barillot ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Meiotic Recombination ◽  
Binding Sites ◽  
Chromosomal Region ◽  
Double Strand Breaks ◽  
Dna Binding Domain ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Genome Wide ◽  
Local Stimulation

ABSTRACT Meiotic recombination is initiated by the formation of programmed DNA double-strand breaks (DSBs) catalyzed by the Spo11 protein. DSBs are not randomly distributed along chromosomes. To better understand factors that control the distribution of DSBs in budding yeast, we have examined the genome-wide binding and cleavage properties of the Gal4 DNA binding domain (Gal4BD)-Spo11 fusion protein. We found that Gal4BD-Spo11 cleaves only a subset of its binding sites, indicating that the association of Spo11 with chromatin is not sufficient for DSB formation. In centromere-associated regions, the centromere itself prevents DSB cleavage by tethered Gal4BD-Spo11 since its displacement restores targeted DSB formation. In addition, we observed that new DSBs introduced by Gal4BD-Spo11 inhibit surrounding DSB formation over long distances (up to 60 kb), keeping constant the number of DSBs per chromosomal region. Together, these results demonstrate that the targeting of Spo11 to new chromosomal locations leads to both local stimulation and genome-wide redistribution of recombination initiation and that some chromosomal regions are inherently cold regardless of the presence of Spo11.

scholarly journals DNA Double-Strand Breaks Coupled with PARP1 and HNRNPA2B1 Binding Sites Flank Coordinately Expressed Domains in Human Chromosomes

PLoS Genetics ◽  
2013 ◽  
Vol 9 (4) ◽  
pp. e1003429 ◽  
Author(s):  
Nickolai A. Tchurikov ◽  
Olga V. Kretova ◽  
Daria M. Fedoseeva ◽  
Dmitri V. Sosin ◽  
Sergei A. Grachev ◽  
...  
Keyword(s):  
Binding Sites ◽  
Double Strand Breaks ◽  
Human Chromosomes ◽  
Dna Double Strand Breaks ◽  
Strand Breaks

scholarly journals DNA Double-Strand Breaks Coupled with PARP1 and HNRNPA2B1 Binding Sites Flank Coordinately Expressed Domains in Human Chromosomes

2019 ◽  
pp. 02-43
Author(s):  
Nickolai A Tchurikov ◽  
Olga V Kretova ◽  
Daria M Fedoseeva ◽  
Dmitri V Sosin ◽  
Sergei A Grachev ◽  
...  
Keyword(s):  
Binding Sites ◽  
Double Strand Breaks ◽  
Human Chromosomes ◽  
Dna Double Strand Breaks ◽  
Strand Breaks

scholarly journals Identification of a signature of evolutionarily conserved stress-induced mutagenesis in cancer

2021 ◽  
Author(s):  
Luis Humberto Cisneros ◽  
Kimberly J Bussey ◽  
Charles Vasque
Keyword(s):  
Double Strand Breaks ◽  
Whole Genome Sequencing Data ◽  
Dna Double Strand Breaks ◽  
Sequencing Data ◽  
Single Nucleotide ◽  
Strand Breaks ◽  
Evolutionarily Conserved ◽  
Induced Mutagenesis ◽  
Genomic Locations ◽  
Inherited Mutations

The clustering of mutations observed in cancer cells is reminiscent of the stress-induced mutagenesis (SIM) response in bacteria. SIM employs error-prone polymerases resulting in mutations concentrated around DNA double-strand breaks with an abundance that decays with genomic distance. We performed a quantitative study on single nucleotide variant calls for whole-genome sequencing data from 1950 tumors and non-inherited mutations from 129 normal samples. We introduce statistical methods to identify mutational clusters and quantify their distribution pattern. Our results show that mutations in both normal and cancer samples are indeed clustered and have shapes indicative of SIM. We found the genomic locations of groups of close mutations are more likely to be prevalent across normal samples than in cancer suggesting loss of regulation over the mutational process during carcinogenesis.

scholarly journals Mouse TEX15 is essential for DNA double-strand break repair and chromosomal synapsis during male meiosis

2008 ◽  
Vol 180 (4) ◽  
pp. 673-679 ◽  
Author(s):  
Fang Yang ◽  
Sigrid Eckardt ◽  
N. Adrian Leu ◽  
K. John McLaughlin ◽  
Peijing Jeremy Wang
Keyword(s):  
Meiotic Recombination ◽  
Strand Break ◽  
Male Meiosis ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Homologous Chromosomes ◽  
Recombination Proteins ◽  
Meiotic Chromosomes ◽  
Dna Double Strand Break

During meiosis, homologous chromosomes undergo synapsis and recombination. We identify TEX15 as a novel protein that is required for chromosomal synapsis and meiotic recombination. Loss of TEX15 function in mice causes early meiotic arrest in males but not in females. Specifically, TEX15-deficient spermatocytes exhibit a failure in chromosomal synapsis. In mutant spermatocytes, DNA double-strand breaks (DSBs) are formed, but localization of the recombination proteins RAD51 and DMC1 to meiotic chromosomes is severely impaired. Based on these data, we propose that TEX15 regulates the loading of DNA repair proteins onto sites of DSBs and, thus, its absence causes a failure in meiotic recombination.

scholarly journals Role of Interleukin33 in Rejuvenation of Aged Neurons and Age-Related Dementias

2021 ◽  
Vol 16 ◽  
pp. 263310552110302
Author(s):  
Yahuan Lou
Keyword(s):  
Oxidative Stress ◽  
Potential Risk ◽  
Middle Age ◽  
Late Onset ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Age Related ◽  
Deficient Mice

Late-onset Alzheimer’s disease (LOAD) is the most common age-related dementia, and its etiology remains unclear. Recent studies have linked abnormal neuronal aging to LOAD. Neurons are non-proliferative, and thus, majority of aged neurons must be rejuvenated through repairing or eliminating damaged molecules to regain their healthy status and functionalities. We discovered a surge of oxidative stress in neurons at middle age in mice. A rapid upregulation of neuronal rejuvenation is vital, while astrocyte-expressed interleukin33 (IL33), an IL1-like cytokine, is critical for this process. Thus, IL33-deficiency cripples the neuronal rejuvenation mechanisms, such as repairing DNA double strand breaks, eliminating damaged molecules by autophagy or by glymphatic drainage. IL33-deficient mice develop tau deposition and age-related dementia following a path similar to LOAD. We hypothesize that any interferences on IL33-initiated rejuvenation process for aged neurons after middle life is a potential risk for LOAD development.

scholarly journals A game of musical chairs: Pro- and anti-resection factors compete for TOPBP1 binding after DNA damage

2017 ◽  
Vol 216 (3) ◽  
pp. 535-537 ◽  
Author(s):  
Kenji Shimada ◽  
Susan M. Gasser
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Binding Sites ◽  
Double Strand Breaks ◽  
Nonhomologous End Joining ◽  
Repair Pathway ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Strand Breaks ◽  
Pathway Regulation

DNA double strand breaks (DSBs) are generally repaired through nonhomologous end joining or homologous recombination. In this issue, Liu et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201607031) report that the conserved scaffold protein TOPBP1Dpb11 provides binding sites for both pro- and anti-resection factors at DSBs, providing insights into repair pathway regulation.

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