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      Novel approach reveals genomic landscapes of single-strand DNA breaks with nucleotide resolution in human cells

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          Abstract

          Single-strand breaks (SSBs) represent the major form of DNA damage, yet techniques to map these lesions genome-wide with nucleotide-level precision are limited. Here, 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 realms of cellular biology, not obtainable with current approaches.

          Abstract

          Single strand breaks represent the most common form of DNA damage yet no methods to map them in a genome-wide fashion at single nucleotide resolution exist. Here the authors develop such a method and apply to uncover patterns of single-strand DNA “breakome” in different biological conditions.

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          Most cited references37

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          Single-strand break repair and genetic disease.

          Hereditary defects in the repair of DNA damage are implicated in a variety of diseases, many of which are typified by neurological dysfunction and/or increased genetic instability and cancer. Of the different types of DNA damage that arise in cells, single-strand breaks (SSBs) are the most common, arising at a frequency of tens of thousands per cell per day from direct attack by intracellular metabolites and from spontaneous DNA decay. Here, the molecular mechanisms and organization of the DNA-repair pathways that remove SSBs are reviewed and the connection between defects in these pathways and hereditary neurodegenerative disease are discussed.
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            Sequencing newly replicated DNA reveals widespread plasticity in human replication timing.

            Faithful transmission of genetic material to daughter cells involves a characteristic temporal order of DNA replication, which may play a significant role in the inheritance of epigenetic states. We developed a genome-scale approach--Repli Seq--to map temporally ordered replicating DNA using massively parallel sequencing and applied it to study regional variation in human DNA replication time across multiple human cell types. The method requires as few as 8,000 cytometry-fractionated cells for a single analysis, and provides high-resolution DNA replication patterns with respect to both cell-cycle time and genomic position. We find that different cell types exhibit characteristic replication signatures that reveal striking plasticity in regional replication time patterns covering at least 50% of the human genome. We also identified autosomal regions with marked biphasic replication timing that include known regions of monoallelic expression as well as many previously uncharacterized domains. Comparison with high-resolution genome-wide profiles of DNaseI sensitivity revealed that DNA replication typically initiates within foci of accessible chromatin comprising clustered DNaseI hypersensitive sites, and that replication time is better correlated with chromatin accessibility than with gene expression. The data collectively provide a unique, genome-wide picture of the epigenetic compartmentalization of the human genome and suggest that cell-lineage specification involves extensive reprogramming of replication timing patterns.
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              Human mutation rate associated with DNA replication timing.

              Eukaryotic DNA replication is highly stratified, with different genomic regions shown to replicate at characteristic times during S phase. Here we observe that mutation rate, as reflected in recent evolutionary divergence and human nucleotide diversity, is markedly increased in later-replicating regions of the human genome. All classes of substitutions are affected, suggesting a generalized mechanism involving replication time-dependent DNA damage. This correlation between mutation rate and regionally stratified replication timing may have substantial evolutionary implications.
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                Author and article information

                Contributors
                cwahlestedt@med.miami.edu
                philippk08@hotmail.com
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                20 December 2019
                20 December 2019
                2019
                : 10
                : 5799
                Affiliations
                [1 ]ISNI 0000 0000 8895 903X, GRID grid.411404.4, Institute of Genomics, School of Biomedical Sciences, , Huaqiao University, ; 668 Jimei Road, Xiamen, 361021 China
                [2 ]ISNI 0000 0004 1758 0435, GRID grid.488542.7, Department of Pathology, , Second Affiliated Hospital of Fujian Medical University, ; Quanzhou, 362000 China
                [3 ]ISNI 0000 0004 1936 8606, GRID grid.26790.3a, Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, , University of Miami Miller School of Medicine, ; 1501 NW 10th Ave, Miami, FL 33136 USA
                [4 ]ISNI 0000 0001 2248 4331, GRID grid.11918.30, Augur Precision Medicine LTD, Scion House, Stirling University Innovation Park, ; Stirling, FK9 4NF UK
                Author information
                http://orcid.org/0000-0002-4992-1025
                http://orcid.org/0000-0002-1986-1754
                http://orcid.org/0000-0003-4471-5916
                Article
                13602
                10.1038/s41467-019-13602-7
                6925131
                31862872
                b6fe43ed-e51c-47b7-a150-ec36b60aa058
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 23 July 2019
                : 11 November 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: 31671382
                Award Recipient :
                Funded by: City of Quanzhou grant 2016Z007
                Categories
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                Custom metadata
                © The Author(s) 2019

                Uncategorized
                genomic analysis,genomics,dna damage and repair
                Uncategorized
                genomic analysis, genomics, dna damage and repair

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