{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T10:33:41Z","timestamp":1790505221826,"version":"4.1.0"},"reference-count":15,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,12,1]],"date-time":"2019-12-01T00:00:00Z","timestamp":1575158400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2019,12,4]],"date-time":"2019-12-04T00:00:00Z","timestamp":1575417600000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS088645"],"award-info":[{"award-number":["R01 NS088645"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Brain"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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 \u2018fused in sarcoma\u2019 (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<jats:sup>2<\/jats:sup> 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 (&gt;\u20092-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\u00a0stem\u00a0cell (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.<\/jats:p>","DOI":"10.1186\/s13041-019-0526-4","type":"journal-article","created":{"date-parts":[[2019,12,4]],"date-time":"2019-12-04T20:03:03Z","timestamp":1575489783000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["RT2 PCR array screening reveals distinct perturbations in DNA damage response signaling in FUS-associated motor neuron disease"],"prefix":"10.1186","volume":"12","author":[{"given":"Haibo","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suganya","family":"Rangaswamy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manohar","family":"Kodavati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joy","family":"Mitra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenting","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika N.","family":"Guerrero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludo","family":"Van Den Bosch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7333-8123","authenticated-orcid":false,"given":"Muralidhar L.","family":"Hegde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,12,4]]},"reference":[{"key":"526_CR1","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.pneurobio.2016.09.004","volume":"145-146","author":"EN Guerrero","year":"2016","unstructured":"Guerrero EN, Wang H, Mitra J, Hegde PM, Stowell SE, Liachko NF, Kraemer BC, Garruto RM, Rao KS, Hegde ML. TDP-43\/FUS in motor neuron disease: complexity and challenges. Prog Neurobiol. 2016;145-146:78\u201397.","journal-title":"Prog Neurobiol"},{"issue":"5918","key":"526_CR2","doi-asserted-by":"publisher","first-page":"1205","DOI":"10.1126\/science.1166066","volume":"323","author":"TJ Kwiatkowski Jr","year":"2009","unstructured":"Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, et al. Mutations in the FUS\/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009;323(5918):1205\u20138.","journal-title":"Science"},{"issue":"5918","key":"526_CR3","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1126\/science.1165942","volume":"323","author":"C Vance","year":"2009","unstructured":"Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009;323(5918):1208\u201311.","journal-title":"Science"},{"key":"526_CR4","doi-asserted-by":"crossref","first-page":"117906951985635","DOI":"10.1177\/1179069519856358","volume":"13","author":"H Wang","year":"2019","unstructured":"Wang H, Hegde ML. New mechanisms of DNA repair defects in fused in sarcoma-associated Neurodegeneration: stage set for DNA repair-based therapeutics? J Exp Neurosci. 2019;13:1179069519856358.","journal-title":"J Exp Neurosci"},{"issue":"4","key":"526_CR5","doi-asserted-by":"publisher","first-page":"175909141454447","DOI":"10.1177\/1759091414544472","volume":"6","author":"Reddy Ranjith Kumar Sama","year":"2014","unstructured":"Sama RR, Ward CL, Bosco DA. Functions of FUS\/TLS from DNA repair to stress response: implications for ALS. ASN Neuro. 2014;6(4):1\u201318.","journal-title":"ASN Neuro"},{"issue":"1","key":"526_CR6","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1093\/nar\/gkt835","volume":"42","author":"SL Rulten","year":"2014","unstructured":"Rulten SL, Rotheray A, Green RL, Grundy GJ, Moore DA, Gomez-Herreros F, Hafezparast M, Caldecott KW. PARP-1 dependent recruitment of the amyotrophic lateral sclerosis-associated protein FUS\/TLS to sites of oxidative DNA damage. Nucleic Acids Res. 2014;42(1):307\u201314.","journal-title":"Nucleic Acids Res"},{"issue":"10","key":"526_CR7","doi-asserted-by":"publisher","first-page":"1383","DOI":"10.1038\/nn.3514","volume":"16","author":"WY Wang","year":"2013","unstructured":"Wang WY, Pan L, Su SC, Quinn EJ, Sasaki M, Jimenez JC, Mackenzie IR, Huang EJ, Tsai LH. Interaction of FUS and HDAC1 regulates DNA damage response and repair in neurons. Nat Neurosci. 2013;16(10):1383\u201391.","journal-title":"Nat Neurosci"},{"issue":"1","key":"526_CR8","doi-asserted-by":"publisher","first-page":"3683","DOI":"10.1038\/s41467-018-06111-6","volume":"9","author":"H Wang","year":"2018","unstructured":"Wang H, Guo W, Mitra J, Hegde PM, Vandoorne T, Eckelmann BJ, Mitra S, Tomkinson AE, Van Den Bosch L, Hegde ML. Mutant FUS causes DNA ligation defects to inhibit oxidative damage repair in amyotrophic lateral sclerosis. Nat Commun. 2018;9(1):3683.","journal-title":"Nat Commun"},{"issue":"4","key":"526_CR9","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1006\/meth.2001.1262","volume":"25","author":"KJ Livak","year":"2001","unstructured":"Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(\u2212Delta Delta C(T)) method. 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Nat Commun. 2015;6:8897.","journal-title":"Nat Commun"}],"container-title":["Molecular Brain"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13041-019-0526-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s13041-019-0526-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13041-019-0526-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,12,3]],"date-time":"2020-12-03T01:43:28Z","timestamp":1606959808000},"score":1,"resource":{"primary":{"URL":"https:\/\/molecularbrain.biomedcentral.com\/articles\/10.1186\/s13041-019-0526-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12]]},"references-count":15,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["526"],"URL":"https:\/\/doi.org\/10.1186\/s13041-019-0526-4","relation":{},"ISSN":["1756-6606"],"issn-type":[{"value":"1756-6606","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12]]},"assertion":[{"value":"29 March 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 November 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 December 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Human ALS and matched control spinal cord tissues were obtained as de-identified specimens from the Department of Veteran\u2019s Affairs Biorepository, USA. Studies on human tissues were conducted in accordance with the ethics board standards at the Department of Veteran\u2019s Affairs and the institutional review board at the Houston Methodist Research Institute (Houston, Texas).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"103"}}