PMID- 31801573
OWN - NLM
STAT- MEDLINE
DCOM- 20200608
LR  - 20200608
IS  - 1756-6606 (Electronic)
IS  - 1756-6606 (Linking)
VI  - 12
IP  - 1
DP  - 2019 Dec 4
TI  - RT(2) PCR array screening reveals distinct perturbations in DNA damage response 
      signaling in FUS-associated motor neuron disease.
PG  - 103
LID - 10.1186/s13041-019-0526-4 [doi]
LID - 103
AB  - Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease that 
      has been linked to defective DNA repair. Many familial ALS patients harbor 
      autosomal dominant mutations in the gene encoding the RNA/DNA binding protein 
      'fused in sarcoma' (FUS) commonly inducing its cytoplasmic mislocalization. 
      Recent reports from our group and others demonstrate a role of FUS in maintaining 
      genome integrity and the DNA damage response (DDR). FUS interacts with many DDR 
      proteins and may regulate their recruitment at damage sites. Given the role of 
      FUS in RNA transactions, here we explore whether FUS also regulates the 
      expression of DDR factors. We performed RT(2) PCR arrays for DNA repair and DDR 
      signaling pathways in CRISPR/Cas9 FUS knockout (KO) and shRNA mediated FUS 
      knockdown (KD) cells, which revealed significant (> 2-fold) downregulation of 
      BRCA1, DNA ligase 4, MSH complex and RAD23B. Importantly, similar perturbations 
      in these factors were also consistent in motor neurons differentiated from an ALS 
      patient-derived induced pluripotent stem cell (iPSC) line with a FUS-P525L 
      mutation, as well as in postmortem spinal cord tissue of sporadic ALS patients 
      with FUS pathology. BRCA1 depletion has been linked to neuronal DNA double-strand 
      breaks (DSBs) accumulation and cognitive defects. The ubiquitin receptor RAD23 
      functions both in nucleotide excision repair and proteasomal protein clearance 
      pathway and is thus linked to neurodegeneration. Together, our study suggests 
      that the FUS pathology perturbs DDR signaling via both its direct role and the 
      effect on the expression of DDR genes. This underscors an intricate connections 
      between FUS, genome instability, and neurodegeneration.
FAU - Wang, Haibo
AU  - Wang H
AD  - Department of Radiation Oncology, Houston Methodist Research Institute, Houston, 
      TX, 77030, USA.
AD  - Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist 
      Neurological Institute, Houston Methodist Hospital, Houston, TX, 77030, USA.
FAU - Rangaswamy, Suganya
AU  - Rangaswamy S
AD  - Department of Radiation Oncology, Houston Methodist Research Institute, Houston, 
      TX, 77030, USA.
FAU - Kodavati, Manohar
AU  - Kodavati M
AD  - Department of Radiation Oncology, Houston Methodist Research Institute, Houston, 
      TX, 77030, USA.
AD  - Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist 
      Neurological Institute, Houston Methodist Hospital, Houston, TX, 77030, USA.
FAU - Mitra, Joy
AU  - Mitra J
AD  - Department of Radiation Oncology, Houston Methodist Research Institute, Houston, 
      TX, 77030, USA.
AD  - Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist 
      Neurological Institute, Houston Methodist Hospital, Houston, TX, 77030, USA.
FAU - Guo, Wenting
AU  - Guo W
AD  - KU Leuven-Department of Neurosciences, Experimental Neurology and Leuven Brain 
      Institute (LBI), 3000, Leuven, Belgium.
AD  - VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, 3000, 
      Leuven, Belgium.
FAU - Guerrero, Erika N
AU  - Guerrero EN
AD  - Department of Radiation Oncology, Houston Methodist Research Institute, Houston, 
      TX, 77030, USA.
FAU - Van Den Bosch, Ludo
AU  - Van Den Bosch L
AD  - KU Leuven-Department of Neurosciences, Experimental Neurology and Leuven Brain 
      Institute (LBI), 3000, Leuven, Belgium.
AD  - VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, 3000, 
      Leuven, Belgium.
FAU - Hegde, Muralidhar L
AU  - Hegde ML
AUID- ORCID: 0000-0001-7333-8123
AD  - Department of Radiation Oncology, Houston Methodist Research Institute, Houston, 
      TX, 77030, USA. mlhegde@houstonmethodist.org.
AD  - Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist 
      Neurological Institute, Houston Methodist Hospital, Houston, TX, 77030, USA. 
      mlhegde@houstonmethodist.org.
AD  - Weill Medical College, New York, NY, 10065, USA. mlhegde@houstonmethodist.org.
LA  - eng
GR  - R01 NS088645/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20191204
PL  - England
TA  - Mol Brain
JT  - Molecular brain
JID - 101468876
RN  - 0 (RNA-Binding Protein FUS)
SB  - IM
MH  - *DNA Damage/genetics
MH  - DNA Repair/genetics
MH  - Gene Expression Regulation
MH  - HEK293 Cells
MH  - Humans
MH  - Motor Neuron Disease/genetics/*metabolism/*pathology
MH  - Motor Neurons/metabolism/pathology
MH  - RNA-Binding Protein FUS/*metabolism
MH  - *Real-Time Polymerase Chain Reaction
MH  - *Signal Transduction
PMC - PMC6894127
OTO - NOTNLM
OT  - Amyotrophic lateral sclerosis
OT  - DNA damage response
OT  - DNA repair
OT  - Motor neuron disease
OT  - RT2 PCR array
COIS- The authors declare that they have no competing interests.
EDAT- 2019/12/06 06:00
MHDA- 2020/06/09 06:00
PMCR- 2019/12/04
CRDT- 2019/12/06 06:00
PHST- 2019/03/29 00:00 [received]
PHST- 2019/11/26 00:00 [accepted]
PHST- 2019/12/06 06:00 [entrez]
PHST- 2019/12/06 06:00 [pubmed]
PHST- 2020/06/09 06:00 [medline]
PHST- 2019/12/04 00:00 [pmc-release]
AID - 10.1186/s13041-019-0526-4 [pii]
AID - 526 [pii]
AID - 10.1186/s13041-019-0526-4 [doi]
PST - epublish
SO  - Mol Brain. 2019 Dec 4;12(1):103. doi: 10.1186/s13041-019-0526-4.