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Motor Neuron Disease-Associated Loss of Nuclear TDP-43 Is Linked to DNA Double-Strand Break Repair Defects

60 Pages Posted: 12 Apr 2018 Publication Status: Review Complete

See all articles by Joy Mitra

Joy Mitra

Houston Methodist Research Institute - Department of Radiation Oncology

Erika N Guerrero

Houston Methodist Research Institute - Department of Radiation Oncology

Pavana M. Hegde

Houston Methodist Research Institute - Department of Radiation Oncology

Nicole F. Liachko

VA Puget Sound Health Care System - Geriatric Research Education and Clinical Center

Velmarini M. Vasquez

Houston Methodist Research Institute - Department of Radiation Oncology

Haibo Wang

Houston Methodist Research Institute - Department of Radiation Oncology

Junling Gao

University of Texas Medical Branch-Galveston - Department of Neuroscience, Cell Biology, and Anatomy

Arvind Pandey

Houston Methodist Research Institute - Department of Radiation Oncology

J. Paul Taylor

St Jude Children’s Research Hospital - Department of Cell and Molecular Biology

Brian C. Kraemer

VA Puget Sound Health Care System - Geriatric Research Education and Clinical Center

Ping Wu

University of Texas Medical Branch-Galveston - Department of Neuroscience, Cell Biology, and Anatomy

Istvan Boldogh

University of Texas Medical Branch-Galveston - Department of Microbiology and Immunology

Ralph M. Garruto

State University of New York (SUNY) - Department of Anthropology

Sankar Mitra

Houston Methodist Research Institute - Department of Radiation Oncology

K.S. Rao

Institute of Scientific Research and High Technology Services (INDICASAT AIP) - Center for Neuroscience

Muralidhar L. Hegde

Houston Methodist Research Institute - Department of Radiation Oncology

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Abstract

Loss of nuclear TDP-43 has been linked to amyotrophic lateral sclerosis (ALS), which also features increased genome damage in affected neurons. Although TDP-43 binds to DNA, its role in the DNA damage response (DDR) has not been investigated. Here, we report that nuclear TDP-43 is a critical component of the DNA double-strand break (DSB) repair machinery in motor neurons. TDP-43 is rapidly recruited at DSB sites where it stably interact with non-homologous end joining (NHEJ)- mediated DSB repair and DDR factors in spinal motor neurons derived from human neural stem cells. Total or nucleus-specific loss of TDP-43 in motor neurons and C. elegans markedly increased genomic DSBs by impairing NHEJ and sensitized cells to DSB stress. TDP-43 pathology strongly correlated with DSB accumulation and DDR activation in the spinal cord of postmortem ALS patients. Our findings link TDP-43 pathology to impaired DSB repair and persistent DDR signaling in motor neuron disease.

Suggested Citation

Mitra, Joy and Guerrero, Erika N and Hegde, Pavana M. and Liachko, Nicole F. and Vasquez, Velmarini M. and Wang, Haibo and Gao, Junling and Pandey, Arvind and Taylor, J. Paul and Kraemer, Brian C. and Wu, Ping and Boldogh, Istvan and Garruto, Ralph M. and Mitra, Sankar and Rao, K.S. and Hegde, Muralidhar L., Motor Neuron Disease-Associated Loss of Nuclear TDP-43 Is Linked to DNA Double-Strand Break Repair Defects (2018). Available at SSRN: https://ssrn.com/abstract=3155763 or http://dx.doi.org/10.2139/ssrn.3155763
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Joy Mitra

Houston Methodist Research Institute - Department of Radiation Oncology

6670 Bertner Ave
Houston, 77030
United States

Erika N Guerrero

Houston Methodist Research Institute - Department of Radiation Oncology

6670 Bertner Ave
Houston, 77030
United States

Pavana M. Hegde

Houston Methodist Research Institute - Department of Radiation Oncology

6670 Bertner Ave
Houston, 77030
United States

Nicole F. Liachko

VA Puget Sound Health Care System - Geriatric Research Education and Clinical Center

1660 S. Columbian Way
Seattle, WA 98106
United States

Velmarini M. Vasquez

Houston Methodist Research Institute - Department of Radiation Oncology

6670 Bertner Ave
Houston, 77030
United States

Haibo Wang

Houston Methodist Research Institute - Department of Radiation Oncology

6670 Bertner Ave
Houston, 77030
United States

Junling Gao

University of Texas Medical Branch-Galveston - Department of Neuroscience, Cell Biology, and Anatomy

Galveston, TX 77555
United States

Arvind Pandey

Houston Methodist Research Institute - Department of Radiation Oncology

6670 Bertner Ave
Houston, 77030
United States

J. Paul Taylor

St Jude Children’s Research Hospital - Department of Cell and Molecular Biology

262 Danny Thomas Place
Memphis, TN 38105
United States

Brian C. Kraemer

VA Puget Sound Health Care System - Geriatric Research Education and Clinical Center

1660 S. Columbian Way
Seattle, WA 98106
United States

Ping Wu

University of Texas Medical Branch-Galveston - Department of Neuroscience, Cell Biology, and Anatomy

Galveston, TX 77555
United States

Istvan Boldogh

University of Texas Medical Branch-Galveston - Department of Microbiology and Immunology

Galveston, TX 77555
United States

Ralph M. Garruto

State University of New York (SUNY) - Department of Anthropology

Binghamton, NY 13902-6000
United States

Sankar Mitra

Houston Methodist Research Institute - Department of Radiation Oncology

6670 Bertner Ave
Houston, 77030
United States

K.S. Rao

Institute of Scientific Research and High Technology Services (INDICASAT AIP) - Center for Neuroscience

Panama

Muralidhar L. Hegde (Contact Author)

Houston Methodist Research Institute - Department of Radiation Oncology ( email )

6670 Bertner Ave
Houston, 77030
United States

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