HELLS and PRDM9 form a Pioneer Complex to Open Chromatin at Meiotic Recombination Hotspots

SUMMARYChromatin 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 modifications, not found at other regulatory elements. HELLS is recruited to hotspots by PRDM9, and is necessary for both histone modifications and DNA accessibility at hotspots. In male mice lacking HELLS, DSBs are retargeted to other sites of open chromatin, leading to germ cell death and sterility. Together, these data provide a model for hotspot activation where HELLS and PRDM9 function as a pioneer complex to create a unique epigenomic environment of open chromatin, permitting correct placement and repair of DSBs.

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RAD6 Promotes Homologous Recombination Repair by Activating the Autophagy-Mediated Degradation of Heterochromatin Protein HP1

Molecular and Cellular Biology ◽

10.1128/mcb.01044-14 ◽

2014 ◽

Vol 35 (2) ◽

pp. 406-416 ◽

Cited By ~ 26

Author(s):

Su Chen ◽

Chen Wang ◽

Luxi Sun ◽

Da-Liang Wang ◽

Lu Chen ◽

...

Keyword(s):

Homologous Recombination ◽

Genome Stability ◽

Chromosomal Rearrangements ◽

Strand Break ◽

Open Chromatin ◽

Dsb Repair ◽

Heterochromatin Protein ◽

Dna Double Strand Break ◽

Recombination Repair ◽

Ubiquitin Conjugating Enzyme

Efficient DNA double-strand break (DSB) repair is critical for the maintenance of genome stability. Unrepaired or misrepaired DSBs cause chromosomal rearrangements that can result in severe consequences, such as tumorigenesis. RAD6 is an E2 ubiquitin-conjugating enzyme that plays a pivotal role in repairing UV-induced DNA damage. Here, we present evidence that RAD6 is also required for DNA DSB repair via homologous recombination (HR) by specifically regulating the degradation of heterochromatin protein 1α (HP1α). Our study indicates that RAD6 physically interacts with HP1α and ubiquitinates HP1α at residue K154, thereby promoting HP1α degradation through the autophagy pathway and eventually leading to an open chromatin structure that facilitates efficient HR DSB repair. Furthermore, bioinformatics studies have indicated that the expression of RAD6 and HP1α exhibits an inverse relationship and correlates with the survival rate of patients.

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Histone modifications and DNA double-strand break repair

Biochemistry and Cell Biology ◽

10.1139/o04-034 ◽

2004 ◽

Vol 82 (4) ◽

pp. 446-452 ◽

Cited By ~ 32

Author(s):

John D Moore ◽

Jocelyn E Krebs

Keyword(s):

Histone Modification ◽

Histone Modifications ◽

Strand Break ◽

Double Strand Break ◽

Double Strand Break Repair ◽

Homologous Sequence ◽

Dna Double Strand Break ◽

Recombination Repair ◽

Break Repair ◽

Gain Access

The roles of different histone modifications have been explored extensively in a number of nuclear processes, particularly in transcriptional regulation. Only recently has the role of histone modification in signaling or facilitating DNA repair begun to be elucidated. DNA broken along both strands in the same region, a double-strand break, is damaged in the most severe way possible and can be the most difficult type of damage to repair accurately. To successfully repair the double-strand break, the cell must gain access to the damaged ends of the DNA and recruit repair factors, and in the case of homologous recombination repair, the cell must also find, colocalize, and gain access to a suitable homologous sequence. In the repair of a double-strand break, the cell must also choose between homologous and non-homologous pathways of repair. Here, we will briefly review the mechanisms of double-strand-break repair, and discuss the known roles of histone modifications in signaling and repairing double-strand breaks.Key words: H23A, double strand break repair, histone modification.

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Tetrameric Ctp1 coordinates DNA binding and DNA bridging in DNA double-strand-break repair

Nature Structural & Molecular Biology ◽

10.1038/nsmb.2945 ◽

2015 ◽

Vol 22 (2) ◽

pp. 158-166 ◽

Cited By ~ 42

Author(s):

Sara N Andres ◽

C Denise Appel ◽

James W Westmoreland ◽

Jessica S Williams ◽

Yvonne Nguyen ◽

...

Keyword(s):

Dna Binding ◽

Strand Break ◽

Double Strand Break ◽

Double Strand Break Repair ◽

Dna Double Strand Break ◽

Break Repair

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Motor neuron disease-associated loss of nuclear TDP-43 is linked to DNA double-strand break repair defects

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1818415116 ◽

2019 ◽

Vol 116 (10) ◽

pp. 4696-4705 ◽

Cited By ~ 54

Author(s):

Joy Mitra ◽

Erika N. Guerrero ◽

Pavana M. Hegde ◽

Nicole F. Liachko ◽

Haibo Wang ◽

...

Keyword(s):

Dna Binding ◽

Motor Neuron ◽

Motor Neuron Disease ◽

Motor Neurons ◽

Strand Break ◽

Double Strand Break ◽

Dsb Repair ◽

Dna Double Strand Break ◽

Sporadic Als ◽

Als Patients

Genome damage and their defective repair have been etiologically linked to degenerating neurons in many subtypes of amyotrophic lateral sclerosis (ALS) patients; however, the specific mechanisms remain enigmatic. The majority of sporadic ALS patients feature abnormalities in the transactivation response DNA-binding protein of 43 kDa (TDP-43), whose nucleo-cytoplasmic mislocalization is characteristically observed in spinal motor neurons. While emerging evidence suggests involvement of other RNA/DNA binding proteins, like FUS in DNA damage response (DDR), the role of TDP-43 in DDR has not been investigated. Here, we report that TDP-43 is a critical component of the nonhomologous end joining (NHEJ)-mediated DNA double-strand break (DSB) repair pathway. TDP-43 is rapidly recruited at DSB sites to stably interact with DDR and NHEJ factors, specifically acting as a scaffold for the recruitment of break-sealing XRCC4-DNA ligase 4 complex at DSB sites in induced pluripotent stem cell-derived motor neurons. shRNA or CRISPR/Cas9-mediated conditional depletion of TDP-43 markedly increases accumulation of genomic DSBs by impairing NHEJ repair, and thereby, sensitizing neurons to DSB stress. Finally, TDP-43 pathology strongly correlates with DSB repair defects, and damage accumulation in the neuronal genomes of sporadic ALS patients and inCaenorhabditis elegansmutant with TDP-1 loss-of-function. Our findings thus link TDP-43 pathology to impaired DSB repair and persistent DDR signaling in motor neuron disease, and suggest that DSB repair-targeted therapies may ameliorate TDP-43 toxicity-induced genome instability in motor neuron disease.

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Faculty Opinions recommendation of Tetrameric Ctp1 coordinates DNA binding and DNA bridging in DNA double-strand-break repair.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725308737.793508850 ◽

2015 ◽

Author(s):

Susan Lees-Miller

Keyword(s):

Dna Binding ◽

Strand Break ◽

Double Strand Break ◽

Double Strand Break Repair ◽

Dna Double Strand Break ◽

Break Repair

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Histone modifications and the DNA double-strand break response

Cell Cycle ◽

10.1080/15384101.2018.1542899 ◽

2018 ◽

Vol 17 (21-22) ◽

pp. 2399-2410 ◽

Cited By ~ 10

Author(s):

Hieu T. Van ◽

Margarida A. Santos

Keyword(s):

Histone Modifications ◽

Strand Break ◽

Double Strand Break ◽

Dna Double Strand Break

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DNA-binding and strand-annealing activities of human Mre11: implications for its roles in DNA double-strand break repair pathways

Nucleic Acids Research ◽

10.1093/nar/29.6.1317 ◽

2001 ◽

Vol 29 (6) ◽

pp. 1317-1325 ◽

Cited By ~ 80

Author(s):

M. de Jager

Keyword(s):

Dna Binding ◽

Strand Break ◽

Double Strand Break ◽

Double Strand Break Repair ◽

Dna Double Strand Break ◽

Repair Pathways ◽

Break Repair ◽

Strand Annealing

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Open chromatin reveals the functional maize genome

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1525244113 ◽

2016 ◽

Vol 113 (22) ◽

pp. E3177-E3184 ◽

Cited By ~ 125

Author(s):

Eli Rodgers-Melnick ◽

Daniel L. Vera ◽

Hank W. Bass ◽

Edward S. Buckler

Keyword(s):

Complex Traits ◽

Nuclear Dna ◽

Regulatory Elements ◽

Micrococcal Nuclease ◽

Open Chromatin ◽

Phenotypic Variance ◽

Maize Genome ◽

Cellular Processes ◽

Recombination Hotspots ◽

Chromatin Structural

Cellular processes mediated through nuclear DNA must contend with chromatin. Chromatin structural assays can efficiently integrate information across diverse regulatory elements, revealing the functional noncoding genome. In this study, we use a differential nuclease sensitivity assay based on micrococcal nuclease (MNase) digestion to discover open chromatin regions in the maize genome. We find that maize MNase-hypersensitive (MNase HS) regions localize around active genes and within recombination hotspots, focusing biased gene conversion at their flanks. Although MNase HS regions map to less than 1% of the genome, they consistently explain a remarkably large amount (∼40%) of heritable phenotypic variance in diverse complex traits. MNase HS regions are therefore on par with coding sequences as annotations that demarcate the functional parts of the maize genome. These results imply that less than 3% of the maize genome (coding and MNase HS regions) may give rise to the overwhelming majority of phenotypic variation, greatly narrowing the scope of the functional genome.

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