Analysis of ionizing radiation induced DNA damage response in human adult stem cells and differentiated neurons

Meador, Jarah A.; Balajee, Adayabalam S.

doi:10.1016/j.mrgentox.2022.503486

Analysis of ionizing radiation induced DNA damage response in human adult stem cells and differentiated neurons

Journal Article · Mon Apr 18 00:00:00 EDT 2022 · Mutation Research/Genetic Toxicology and Environmental Mutagenesis

DOI:https://doi.org/10.1016/j.mrgentox.2022.503486· OSTI ID:1977461

Meador, Jarah A. ^[1]; Balajee, Adayabalam S. ^[2]

San Antonio, TX (United States); OSTI
Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)

Findings of neurodegenerative features associated with human radiosensitive syndromes such as Ataxia telangiectasia suggest that DNA repair efficiency is crucial for maintaining the functional integrity of central nervous system. To gain a better understanding of ionizing radiation (IR) induced DNA damage response in undifferentiated and differentiated neural cell types and to evaluate the role of ATM in DNA double strand break (DSB) repair, an in vitro human neural cell differentiation model system was utilized in this study. As compared to adult stem cells, differentiated neurons displayed an attenuated DSB repair response (as judged by the persistence of 53BP1 foci) after IR exposure and the attenuation was even more pronounced in stem cells and neurons after suppression of ATM (Ataxia Telangiectasia Mutated) gene product suggesting the importance of ATM for an optimal DSB repair efficiency in human neural cell types. In corroboration with an attenuated DNA damage response, a sharp decline in the expression levels of several DSB repair genes was observed in neurons. Furthermore, our results suggest that cellular differentiation modulates the expression of several genes thereby compromising the DSB repair fidelity in post mitotic neurons. Further studies are required to verify whether or not ATM mediated exacerbation of DNA repair deficiency in differentiated neurons leads to neurodegeneration.

View Accepted Manuscript (DOE)

Research Organization:: Columbia University, New York, NY (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: FG02-05ER64055

OSTI ID:: 1977461

Alternate ID(s):: OSTI ID: 1867509

Journal Information:: Mutation Research/Genetic Toxicology and Environmental Mutagenesis, Journal Name: Mutation Research/Genetic Toxicology and Environmental Mutagenesis Journal Issue: C Vol. 878; ISSN 1383-5718

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

References (32)

Differentiation-Related Response to DNA Breaks in Human Mesenchymal Stem Cells Oliver, Lisa; Hue, Erika; Séry, Quentin Stem Cells, Vol. 31, Issue 4 https://doi.org/10.1002/stem.1336	journal	March 2013
DNA Ligase IV Deficiency in Mice Leads to Defective Neurogenesis and Embryonic Lethality via the p53 Pathway Frank, Karen M.; Sharpless, Norman E.; Gao, Yijie Molecular Cell, Vol. 5, Issue 6 https://doi.org/10.1016/S1097-2765(00)80264-6	journal	June 2000
DNA double-strand breaks as drivers of neural genomic change, function, and disease Alt, Frederick W.; Schwer, Bjoern DNA Repair, Vol. 71 https://doi.org/10.1016/j.dnarep.2018.08.019	journal	November 2018
More efficient repair of DNA double-strand breaks in skeletal muscle stem cells compared to their committed progeny Vahidi Ferdousi, Leyla; Rocheteau, Pierre; Chayot, Romain Stem Cell Research, Vol. 13, Issue 3 https://doi.org/10.1016/j.scr.2014.08.005	journal	November 2014
Differentiation of Human Induced Pluripotent or Embryonic Stem Cells Decreases the DNA Damage Repair by Homologous Recombination Mujoo, Kalpana; Pandita, Raj K.; Tiwari, Anjana Stem Cell Reports, Vol. 9, Issue 5 https://doi.org/10.1016/j.stemcr.2017.10.002	journal	November 2017
DNA-damage response, survival and differentiation in vitro of a human neural stem cell line in relation to ATM expression Carlessi, L.; De Filippis, L.; Lecis, D. Cell Death & Differentiation, Vol. 16, Issue 6 https://doi.org/10.1038/cdd.2009.10	journal	February 2009
Functional and molecular defects of hiPSC-derived neurons from patients with ATM deficiency Carlessi, L.; Poli, E. Fusar; Bechi, G. Cell Death & Disease, Vol. 5, Issue 7 https://doi.org/10.1038/cddis.2014.310	journal	July 2014
53BP1 promotes ATM activity through direct interactions with the MRN complex Lee, Ji-Hoon; Goodarzi, Aaron A.; Jeggo, Penny A. The EMBO Journal, Vol. 29, Issue 3 https://doi.org/10.1038/emboj.2009.372	journal	December 2009
Roles of ATM and NBS1 in chromatin structure modulation and DNA double-strand break repair Berkovich, Elijahu; Monnat, Raymond J.; Kastan, Michael B. Nature Cell Biology, Vol. 9, Issue 6 https://doi.org/10.1038/ncb1599	journal	May 2007
Bcl-2 and accelerated DNA repair mediates resistance of hair follicle bulge stem cells to DNA-damage-induced cell death Sotiropoulou, Panagiota A.; Candi, Aurélie; Mascré, Guilhem Nature Cell Biology, Vol. 12, Issue 6 https://doi.org/10.1038/ncb2059	journal	May 2010
Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-β Suberbielle, Elsa; Sanchez, Pascal E.; Kravitz, Alexxai V. Nature Neuroscience, Vol. 16, Issue 5 https://doi.org/10.1038/nn.3356	journal	March 2013
Maintaining genome stability in the nervous system McKinnon, Peter J. Nature Neuroscience, Vol. 16, Issue 11 https://doi.org/10.1038/nn.3537	journal	October 2013
ATM and CDK2 control chromatin remodeler CSB to inhibit RIF1 in DSB repair pathway choice Batenburg, Nicole L.; Walker, John R.; Noordermeer, Sylvie M. Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/s41467-017-02114-x	journal	December 2017
DNA double strand break repair and chromosomal translocation: Lessons from animal models Ferguson, David O.; Alt, Frederick W. Oncogene, Vol. 20, Issue 40 https://doi.org/10.1038/sj.onc.1204767	journal	September 2001
Genetic interactions between ATM and the nonhomologous end-joining factors in genomic stability and development Sekiguchi, JoAnn; Ferguson, David O.; Chen, Hua Tang Proceedings of the National Academy of Sciences, Vol. 98, Issue 6 https://doi.org/10.1073/pnas.051632098	journal	March 2001
Tumor Suppressor P53 Binding Protein 1 (53bp1) Is Involved in DNA Damage–Signaling Pathways Rappold, Irene; Iwabuchi, Kuniyoshi; Date, Takayasu Journal of Cell Biology, Vol. 153, Issue 3 https://doi.org/10.1083/jcb.153.3.613	journal	April 2001
Mutant huntingtin impairs Ku70-mediated DNA repair Enokido, Yasushi; Tamura, Takuya; Ito, Hikaru Journal of Cell Biology, Vol. 189, Issue 3 https://doi.org/10.1083/jcb.200905138	journal	May 2010
Molecular Regulation of DNA Damage-Induced Apoptosis in Neurons of Cerebral Cortex Martin, L. J.; Liu, Z.; Pipino, J. Cerebral Cortex, Vol. 19, Issue 6 https://doi.org/10.1093/cercor/bhn167	journal	September 2008
Repair kinetics of DNA double-strand breaks and incidence of apoptosis in mouse neural stem/progenitor cells and their differentiated neurons exposed to ionizing radiation Kashiwagi, Hiroki; Shiraishi, Kazunori; Sakaguchi, Kenta Journal of Radiation Research, Vol. 59, Issue 3 https://doi.org/10.1093/jrr/rrx089	journal	January 2018
ATM-dependent pathways of chromatin remodelling and oxidative DNA damage responses Berger, N. Daniel; Stanley, Fintan K. T.; Moore, Shaun Philosophical Transactions of the Royal Society B: Biological Sciences, Vol. 372, Issue 1731 https://doi.org/10.1098/rstb.2016.0283	journal	August 2017
Nonhomologous End-joining Proteins Are Required for V(D)J Recombination, Normal Growth, and Neurogenesis Sekiguchi, J. M.; Gao, Y.; Gu, Y. Cold Spring Harbor Symposia on Quantitative Biology, Vol. 64, Issue 0 https://doi.org/10.1101/sqb.1999.64.169	journal	January 1999
ATM and ATR Substrate Analysis Reveals Extensive Protein Networks Responsive to DNA Damage Matsuoka, S.; Ballif, B. A.; Smogorzewska, A. Science, Vol. 316, Issue 5828 https://doi.org/10.1126/science.1140321	journal	May 2007
ATM and the Molecular Pathogenesis of Ataxia Telangiectasia McKinnon, Peter J. Annual Review of Pathology: Mechanisms of Disease, Vol. 7, Issue 1 https://doi.org/10.1146/annurev-pathol-011811-132509	journal	February 2012
ATR/ATM-Mediated Phosphorylation of BRCA1 T1394 Promotes Homologous Recombinational Repair and G2–M Checkpoint Maintenance Foo, Tzeh K.; Vincelli, Gabriele; Huselid, Eric Cancer Research, Vol. 81, Issue 18 https://doi.org/10.1158/0008-5472.CAN-20-2723	journal	July 2021
Targeting BRG1 Chromatin Remodeler via Its Bromodomain for Enhanced Tumor Cell Radiosensitivity In Vitro and In Vivo Kwon, Su-Jung; Lee, Seul-Ki; Na, Juri Molecular Cancer Therapeutics, Vol. 14, Issue 2 https://doi.org/10.1158/1535-7163.MCT-14-0372	journal	December 2014
Maintenance of active chromatin states by HMGN2 is required for stem cell identity in a pluripotent stem cell model Garza-Manero, Sylvia; Sindi, Abdulmajeed Abdulghani A.; Mohan, Gokula Epigenetics & Chromatin, Vol. 12, Issue 1 https://doi.org/10.1186/s13072-019-0320-7	journal	December 2019
Dancing on Damaged Chromatin: Functions of ATM and the RAD50/MRE11/NBS1 Complex in Cellular Responses to DNA Damage Iijima, Kenta; Ohara, Maki; Seki, Ryota Journal of Radiation Research, Vol. 49, Issue 5 https://doi.org/10.1269/jrr.08065	journal	January 2008
DNA Damage Responses in Human Induced Pluripotent Stem Cells and Embryonic Stem Cells Momcilovic, Olga; Knobloch, Leah; Fornsaglio, Jamie PLoS ONE, Vol. 5, Issue 10 https://doi.org/10.1371/journal.pone.0013410	journal	October 2010
ATM Alters the Otherwise Robust Chromatin Mobility at Sites of DNA Double-Strand Breaks (DSBs) in Human Cells Becker, Annabelle; Durante, Marco; Taucher-Scholz, Gisela PLoS ONE, Vol. 9, Issue 3 https://doi.org/10.1371/journal.pone.0092640	journal	March 2014
DNA-PKcs, ATM, and ATR Interplay Maintains Genome Integrity during Neurogenesis Enriquez-Rios, Vanessa; Dumitrache, Lavinia C.; Downing, Susanna M. The Journal of Neuroscience, Vol. 37, Issue 4 https://doi.org/10.1523/JNEUROSCI.4213-15.2016	journal	December 2016
ATM-independent, high-fidelity nonhomologous end joining predominates in human embryonic stem cells Adams, Bret R.; Hawkins, Amy J.; Povirk, Lawrence F. Aging, Vol. 2, Issue 9 https://doi.org/10.18632/aging.100197	journal	September 2010
Effect of Chromatin Structure on the Extent and Distribution of DNA Double Strand Breaks Produced by Ionizing Radiation; Comparative Study of hESC and Differentiated Cells Lines Venkatesh, Priyanka; Panyutin, Irina; Remeeva, Evgenia International Journal of Molecular Sciences, Vol. 17, Issue 1 https://doi.org/10.3390/ijms17010058	journal	January 2016

Similar Records

ATM–dependent phosphorylation of CHD7 regulates morphogenesis-coupled DSB stress response in fetal radiation exposure

Journal Article · Mon Apr 10 20:00:00 EDT 2023 · Molecular Biology of the Cell · OSTI ID:2424388

Novel Smad proteins localize to IR-induced double-strand breaks: interplay between TGFβ and ATM pathways

Journal Article · Tue Dec 04 19:00:00 EST 2012 · Nucleic Acids Research · OSTI ID:1625498

DNA damage preceding dopamine neuron degeneration in A53T human α-synuclein transgenic mice

Journal Article · Thu Dec 01 23:00:00 EST 2016 · Biochemical and Biophysical Research Communications · OSTI ID:22696722

Related Subjects

53 binding protein 1
59 BASIC BIOLOGICAL SCIENCES
Ataxia telangiectasia
Biotechnology & Applied Microbiology
DNA damage response
Differentiated neuronal cells
Genetics & Heredity
Human adult stem cells
Ionizing radiation
Neurodegeneration
Toxicology

Analysis of ionizing radiation induced DNA damage response in human adult stem cells and differentiated neurons

Citation Formats

References (32)

Similar Records

Related Subjects