Cell transcriptional state alters genomic patterns of DNA double-strand break repair in human astrocytes

Raymund L. Yong (), Chunzhang Yang, Jie Lu, Huaien Wang, Cody D. Schlaff, Anita Tandle, Christian A. Graves, Abdel G. Elkahloun, Xiaoyuan Chen, Zhengping Zhuang and Russell R. Lonser ()
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Raymund L. Yong: Icahn School of Medicine at Mount Sinai
Chunzhang Yang: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health
Jie Lu: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health
Huaien Wang: Icahn School of Medicine at Mount Sinai
Cody D. Schlaff: Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Anita Tandle: Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Christian A. Graves: Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Abdel G. Elkahloun: Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health
Xiaoyuan Chen: Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health
Zhengping Zhuang: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health
Russell R. Lonser: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: Abstract The misrepair of DNA double-strand breaks in close spatial proximity within the nucleus can result in chromosomal rearrangements that are important in the pathogenesis of haematopoietic and solid malignancies. It is unknown why certain epigenetic states, such as those found in stem or progenitor cells, appear to facilitate neoplastic transformation. Here we show that altering the transcriptional state of human astrocytes alters patterns of DNA damage repair from ionizing radiation at a gene locus-specific and genome-wide level. Astrocytes induced into a reactive state exhibit increased DNA repair, compared with non-reactive cells, in actively transcribed chromatin after irradiation. In mapping these repair sites, we identify misrepair events and repair hotspots that are unique to each state. The precise characterization of genomic regions susceptible to mutation in specific transcriptional states provides new opportunities for addressing clonal evolution in solid cancers, in particular those where double-strand break induction is a cornerstone of clinical intervention.

Date: 2014
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DOI: 10.1038/ncomms6799

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