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Nat Commun. 2018 Sep 11;9(1):3683. doi: 10.1038/s41467-018-06111-6.

Mutant FUS causes DNA ligation defects to inhibit oxidative damage repair in Amyotrophic Lateral Sclerosis.

Author information

1
Department of Radiation Oncology, Houston Methodist Research Institute, Houston, 77030, TX, USA.
2
KU Leuven-Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), Leuven, 3000, Belgium.
3
VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, 3000, Belgium.
4
Texas A&M Health Science Center, College of Medicine, Bryan, 77807, TX, USA.
5
Weill Medical College, New York, 10065, NY, USA.
6
Departments of Internal Medicine, and Molecular Genetics and Microbiology and University of New Mexico Comprehensive Cancer Center, University of New Mexico, Albuquerque, 87131, NM, USA.
7
Department of Radiation Oncology, Houston Methodist Research Institute, Houston, 77030, TX, USA. mlhegde@houstonmethodist.org.
8
Weill Medical College, New York, 10065, NY, USA. mlhegde@houstonmethodist.org.
9
Houston Methodist Neurological Institute, Institute of Academic Medicine, Houston Methodist, Houston, 77030, TX, USA. mlhegde@houstonmethodist.org.

Abstract

Genome damage and defective repair are etiologically linked to neurodegeneration. However, the specific mechanisms involved remain enigmatic. Here, we identify defects in DNA nick ligation and oxidative damage repair in a subset of amyotrophic lateral sclerosis (ALS) patients. These defects are caused by mutations in the RNA/DNA-binding protein FUS. In healthy neurons, FUS protects the genome by facilitating PARP1-dependent recruitment of XRCC1/DNA Ligase IIIα (LigIII) to oxidized genome sites and activating LigIII via direct interaction. We discover that loss of nuclear FUS caused DNA nick ligation defects in motor neurons due to reduced recruitment of XRCC1/LigIII to DNA strand breaks. Moreover, DNA ligation defects in ALS patient-derived iPSC lines carrying FUS mutations and in motor neurons generated therefrom are rescued by CRISPR/Cas9-mediated correction of mutation. Our findings uncovered a pathway of defective DNA ligation in FUS-linked ALS and suggest that LigIII-targeted therapies may prevent or slow down disease progression.

PMID:
30206235
PMCID:
PMC6134028
DOI:
10.1038/s41467-018-06111-6
[Indexed for MEDLINE]
Free PMC Article

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