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Proc Natl Acad Sci U S A. 2016 Nov 29;113(48):E7701-E7709. Epub 2016 Nov 14.

Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage.

Author information

1
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115; sarah_hill@dfci.harvard.edu david_livingston@dfci.harvard.edu.
2
Department of Genetics, Harvard Medical School, Boston, MA 02215.
3
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215.
4
Department of Stem Cell and Regenerative Biology, The Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138.
5
Department of Pathology, Massachusetts General Hospital, Boston, MA 02114.
6
The Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142.
7
Confocal and Light Microscopy Facility, Dana-Farber Cancer Institute, Boston, MA 02215.
8
Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215.
9
Department of Medicine, Harvard Medical School, Boston, MA 02215.
10
Department of Genetics, Harvard Medical School, Boston, MA 02215; sarah_hill@dfci.harvard.edu david_livingston@dfci.harvard.edu.

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron dysfunction disease that leads to paralysis and death. There is currently no established molecular pathogenesis pathway. Multiple proteins involved in RNA processing are linked to ALS, including FUS and TDP43, and we propose a disease mechanism in which loss of function of at least one of these proteins leads to an accumulation of transcription-associated DNA damage contributing to motor neuron cell death and progressive neurological symptoms. In support of this hypothesis, we find that FUS or TDP43 depletion leads to increased sensitivity to a transcription-arresting agent due to increased DNA damage. Thus, these proteins normally contribute to the prevention or repair of transcription-associated DNA damage. In addition, both FUS and TDP43 colocalize with active RNA polymerase II at sites of DNA damage along with the DNA damage repair protein, BRCA1, and FUS and TDP43 participate in the prevention or repair of R loop-associated DNA damage, a manifestation of aberrant transcription and/or RNA processing. Gaining a better understanding of the role(s) that FUS and TDP43 play in transcription-associated DNA damage could shed light on the mechanisms underlying ALS pathogenesis.

KEYWORDS:

ALS; DNA damage response; R loop; transcription

PMID:
27849576
PMCID:
PMC5137757
DOI:
10.1073/pnas.1611673113
[Indexed for MEDLINE]
Free PMC Article

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