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000141597 1001_ $$0P:(DE-2719)2812581$$aNihei, Yoshihiro$$b0$$eFirst author$$udzne
000141597 245__ $$aPoly-glycine-alanine exacerbates C9orf72 repeat expansion-mediated DNA damage via sequestration of phosphorylated ATM and loss of nuclear hnRNPA3.
000141597 260__ $$aHeidelberg$$bSpringer$$c2020
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000141597 520__ $$aRepeat expansion in C9orf72 causes amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Expanded sense and antisense repeat RNA transcripts in C9orf72 are translated into five dipeptide-repeat proteins (DPRs) in an AUG-independent manner. We previously identified the heterogeneous ribonucleoprotein (hnRNP) A3 as an interactor of the sense repeat RNA that reduces its translation into DPRs. Furthermore, we found that hnRNPA3 is depleted from the nucleus and partially mislocalized to cytoplasmic poly-GA inclusions in C9orf72 patients, suggesting that poly-GA sequesters hnRNPA3 within the cytoplasm. We now demonstrate that hnRNPA3 also binds to the antisense repeat RNA. Both DPR production and deposition from sense and antisense RNA repeats are increased upon hnRNPA3 reduction. All DPRs induced DNA double strand breaks (DSB), which was further enhanced upon reduction of hnRNPA3. Poly-glycine-arginine and poly-proline-arginine increased foci formed by phosphorylated Ataxia Telangiectasia Mutated (pATM), a major sensor of DSBs, whereas poly-glycine-alanine (poly-GA) evoked a reduction of pATM foci. In dentate gyri of C9orf72 patients, lower nuclear hnRNPA3 levels were associated with increased DNA damage. Moreover, enhanced poly-GA deposition correlated with reduced pATM foci. Since cytoplasmic pATM deposits partially colocalized with poly-GA deposits, these results suggest that poly-GA, the most frequent DPR observed in C9orf72 patients, differentially causes DNA damage and that poly-GA selectively sequesters pATM in the cytoplasm inhibiting its recruitment to sites of DNA damage. Thus, mislocalization of nuclear hnRNPA3 caused by poly-GA leads to increased poly-GA production, which partially depletes pATM, and consequently enhances DSB.
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000141597 542__ $$2Crossref$$i2019-10-23$$uhttps://creativecommons.org/licenses/by/4.0
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000141597 650_2 $$2MeSH$$aAged
000141597 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: genetics
000141597 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: metabolism
000141597 650_2 $$2MeSH$$aAtaxia Telangiectasia Mutated Proteins: metabolism
000141597 650_2 $$2MeSH$$aC9orf72 Protein: genetics
000141597 650_2 $$2MeSH$$aDNA Damage: genetics
000141597 650_2 $$2MeSH$$aDinucleotide Repeats: physiology
000141597 650_2 $$2MeSH$$aFemale
000141597 650_2 $$2MeSH$$aFrontotemporal Lobar Degeneration: genetics
000141597 650_2 $$2MeSH$$aFrontotemporal Lobar Degeneration: metabolism
000141597 650_2 $$2MeSH$$aHeterogeneous-Nuclear Ribonucleoprotein Group A-B: metabolism
000141597 650_2 $$2MeSH$$aHumans
000141597 650_2 $$2MeSH$$aMale
000141597 650_2 $$2MeSH$$aMiddle Aged
000141597 650_2 $$2MeSH$$aPhosphorylation
000141597 7001_ $$aMori, Kohji$$b1
000141597 7001_ $$aWerner, Georg$$b2
000141597 7001_ $$0P:(DE-2719)2811333$$aArzberger, Thomas$$b3$$udzne
000141597 7001_ $$0P:(DE-2719)2811347$$aZhou, Qihui$$b4$$udzne
000141597 7001_ $$0P:(DE-2719)2811528$$aKhosravi, Bahram$$b5$$udzne
000141597 7001_ $$aJaptok, Julia$$b6
000141597 7001_ $$0P:(DE-2719)2811732$$aHermann, Andreas$$b7$$udzne
000141597 7001_ $$aSommacal, Andreas$$b8
000141597 7001_ $$aWeber, Markus$$b9
000141597 7001_ $$aDegeneration, German Consortium for Frontotemporal Lobar$$b10
000141597 7001_ $$aAlliance, Bavarian Brain Banking$$b11
000141597 7001_ $$0P:(DE-HGF)0$$aKamp, Frits$$b12
000141597 7001_ $$0P:(DE-HGF)0$$aNuscher, Brigitte$$b13
000141597 7001_ $$0P:(DE-2719)2231621$$aEdbauer, Dieter$$b14$$udzne
000141597 7001_ $$0P:(DE-2719)2202037$$aHaass, Christian$$b15$$eLast author$$udzne
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