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| Status |
Public on Mar 25, 2021 |
| Title |
Neuronal Enhancers are Hotspots for DNA Single-Strand Break Repair [SEAL] |
| Organism |
Homo sapiens |
| Experiment type |
Other
Methylation profiling by high throughput sequencing
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| Summary |
Defects in DNA repair frequently lead to neurodevelopmental and neurodegenerative diseases, underscoring the particular importance of DNA repair in long-lived post-mitotic neurons. The cellular genome is subjected to a constant barrage of endogenous DNA damage, but surprisingly little is known about the identity of the lesion(s) that accumulate in neurons and whether they accrue throughout the genome or at specific loci. Here, we show that post-mitotic neurons accumulate unexpectedly high levels of DNA single-strand breakage at specific sites within the genome. Genome-wide mapping reveals that these single-strand breaks (SSBs) are located within enhancers at or near to CpG dinucleotides and sites of DNA demethylation, and are repaired by PARP1 and XRCC1-dependent mechanisms. Notably, deficiencies in XRCC1-dependent short-patch repair elevate the extent of DNA repair synthesis at neuronal enhancers, whereas deficiencies in long-patch repair reduce synthesis, suggesting that the high steady-state level of SSB repair in neuronal enhancers is sustained by both short-patch and long-patch processes. These data provide the first evidence of site- and cell type-specific SSB repair, revealing unexpected levels of localized and continuous DNA single-strand breakage in neurons. In addition, these data suggest an explanation for the neurodegenerative phenotypes that occur in patients with defective SSB repair.
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| Overall design |
We developed synthesis-associated with repair sequencing (SAR) to detect DNA repair in postmotitic neuron cells. Combined with ChIP-seqs, SEAL-seq, END-seq and HiC, we were able to study the DNA damage and its repair mechansim in neurons.
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| Contributor(s) |
Wu W, Hill SE, Nathan WJ, Paiano J, Callen E, Wang D, Shinoda K, van Wietmarschen N, Colón-Mercado JM, Zong D, de Pace R, Shih H, Coon S, Parsadanian M, Pavani R, Hanzlikova H, Park S, Jung SK, McHugh PJ, Canela A, Chen C, Casellas R, Caldecott KW, Ward ME, Nussenzweig A |
| Citation(s) |
33767446 |
| Submission date |
Feb 22, 2021 |
| Last update date |
Jun 26, 2021 |
| Contact name |
Wei Wu |
| Organization name |
National Cancer Institute
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| Department |
Center for Cancer Research
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| Lab |
Laboratory of Genome Integrity
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| Street address |
9000 Rockville Pike
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| City |
Bethesda |
| State/province |
MD |
| ZIP/Postal code |
20892 |
| Country |
USA |
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| Platforms (1) |
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| Samples (6)
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| This SubSeries is part of SuperSeries: |
| GSE167259 |
Neuronal Enhancers are Hotspots for DNA Single-Strand Break Repair |
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| Relations |
| BioProject |
PRJNA704028 |
| SRA |
SRP307553 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE167258_RAW.tar |
1.8 Gb |
(http)(custom) |
TAR (of BW) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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