Hotspots of single-strand DNA "breakome" are enriched at transcriptional start sites of genes
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE190735 | GEO | 2022/08/18
REPOSITORIES: GEO
Similar Datasets
Project description:Single strand breaks (SSBs) represent the major form of DNA damage, yet no technique exists to map these lesions genome-wide with nucleotide-level precision. Herein, we present a method, termed SSiNGLe, and demonstrate its utility to explore the distribution and dynamic changes in genome-wide SSBs in response to different biological and environmental stimuli. We validate SSiNGLe using two very distinct sequencing techniques and apply it to derive global profiles of SSBs in different biological states. Strikingly, we show that patterns of SSBs in the genome are non-random, specific to different biological states, enriched in regulatory elements, exons, introns, specific types of repeats and exhibit differential preference for the template strand between exons and introns. Furthermore, we show that breaks likely contribute to naturally occurring sequence variants. Finally, we demonstrate strong links between SSB patterns and age. Overall, SSiNGLe provides access to unexplored realm of cellular biology, not obtainable with current approaches.
2019-12-31 | GSE139011 | GEO
Project description: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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Project description: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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Project description: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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Project description: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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Project description: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.
2021-03-25 | GSE167254 | GEO
Project description: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.
2021-03-25 | GSE167252 | GEO
Project description: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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Project description:DNA topoisomerases are required to resolve DNA topological stress. Despite this essential role, abortive topoisomerase activity generates aberrant protein-linked DNA breaks, jeopardising genome stability. Here, to understand the genomic distribution and mechanisms underpinning topoisomerase-induced DNA breaks, we map Top2 DNA cleavage with strand-specific nucleotide resolution across the S. cerevisiae and human genomes - and use the meiotic Spo11 protein to validate the broad applicability of this method to explore the role of diverse topoisomerase family members. Our data characterises Mre11-dependent repair in yeast, and defines two strikingly different fractions of Top2 activity in humans: tightly localised CTCF-proximal, and broadly distributed transcription-proximal, the latter correlated with gene length and expression. Moreover, single nucleotide accuracy enables us to reveal the influence primary DNA sequence has upon Top2 cleavage - distinguishing canonical DNA double-strand breaks (DSBs) from a major population of DNA single-strand breaks (SSBs) induced by etoposide (VP16) in vivo.
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Project description:DNA topoisomerases are required to resolve DNA topological stress. Despite this essential role, abortive topoisomerase activity generates aberrant protein-linked DNA breaks, jeopardising genome stability. Here, to understand the genomic distribution and mechanisms underpinning topoisomerase-induced DNA breaks, we map Top2 DNA cleavage with strand-specific nucleotide resolution across the S. cerevisiae and human genomes—and use the meiotic Spo11 protein to validate the broad applicability of this method to explore the role of diverse topoisomerase family members. Our data characterises Mre11-dependent repair in yeast and defines two strikingly different fractions of Top2 activity in humans: tightly localised CTCF-proximal, and broadly distributed transcription-proximal, the latter correlated with gene length and expression. Moreover, single nucleotide accuracy reveals the influence primary DNA sequence has upon Top2 cleavage—distinguishing sites likely to form canonical DNA double-strand breaks (DSBs) from those predisposed to form strand-biased DNA single-strand breaks (SSBs) induced by etoposide (VP16) in vivo.
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