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Poly-glycine–alanine exacerbates C9orf72 repeat expansion-mediated DNA damage via sequestration of phosphorylated ATM and loss of nuclear hnRNPA3
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Poly-glycine–alanine exacerbates C9orf72 repeat expansion-mediated DNA damage via sequestration of phosphorylated ATM and loss of nuclear hnRNPA3
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Journal Article
Poly-glycine–alanine exacerbates C9orf72 repeat expansion-mediated DNA damage via sequestration of phosphorylated ATM and loss of nuclear hnRNPA3
2020
Overview
Repeat 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.
Publisher
Springer Berlin Heidelberg,Springer,Springer Nature B.V
Subject
/ Alanine
/ Amyotrophic lateral sclerosis
/ Amyotrophic Lateral Sclerosis - genetics
/ Amyotrophic Lateral Sclerosis - metabolism
/ Arginine
/ Ataxia telangiectasia mutated protein
/ Ataxia Telangiectasia Mutated Proteins - metabolism
/ Dinucleotide Repeats - physiology
/ DNA
/ Ethylenediaminetetraacetic acid
/ Female
/ Frontotemporal Lobar Degeneration - genetics
/ Frontotemporal Lobar Degeneration - metabolism
/ Glycine
/ Heterogeneous-Nuclear Ribonucleoprotein Group A-B - metabolism
/ Humans
/ Male
/ Medicine
/ Proline
/ Proteins
/ RNA
