Divergent FUS phosphorylation in primate and mouse cells following double-strand DNA damage

NEUROBIOLOGY OF DISEASE

卷:146

Article

Johnson, Michelle A.^1,2  Deng, Qiudong^1,2  Taylor, Georgia^1,2  McEachin, Zachary T.^2,4,5  Chan, Anthony W. S.^2,6,7  Root, Jessica^1,2  Bassell, Gary J.^2,4,5  Kukar, Thomas^1,2,3 

[1] Emory Univ, Sch Med, Dept Pharmacol & Chem Biol, Atlanta, GA USA

[2] Emory Univ, Sch Med, Ctr Neurodegenerat Dis, Atlanta, GA USA

[3] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA

[4] Emory Univ, Sch Med, Dept Cell Biol, Atlanta, GA USA

[5] Emory Univ, Sch Med, Lab Translat Cell Biol, Atlanta, GA USA

[6] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA

[7] Yerkes Natl Primate Res Ctr, Div Neuropharmacol & Neurol Dis, 954 Gatewood Rd NE, Atlanta, GA USA

关键词: Frontotemporal dementia (FTD);    Amyotrophic lateral sclerosis (ALS);    Fused in sarcoma (FUS);    DNA-dependent protein kinase (DNA-PK);    DNA damage;    Phosphorylation;    Calicheamicin gamma 1 (CLM);    Species specific response;   

DOI  :  10.1016/j.nbd.2020.105085

来源: Elsevier

【 摘 要 】

Fused in sarcoma (FUS) is a RNA/DNA protein involved in multiple nuclear and cytoplasmic functions including transcription, splicing, mRNA trafficking, and stress granule formation. To accomplish these many functions, FUS must shuttle between cellular compartments in a highly regulated manner. When shuttling is disrupted, FUS abnormally accumulates into cytoplasmic inclusions that can be toxic. Disrupted shuttling of FUS into the nucleus is a hallmark of similar to 10% of frontotemporal lobar degeneration (FTLD) cases, the neuropathology that underlies frontotemporal dementia (FTD). Multiple pathways are known to disrupt nuclear/cytoplasmic shuttling of FUS. In earlier work, we discovered that double-strand DNA breaks (DSBs) trigger DNA-dependent protein kinase (DNA-PK) to phosphorylate FUS (p-FUS) at N-terminal residues leading to the cytoplasmic accumulation of FUS. Therefore, DNA damage may contribute to the development of FTLD pathology with FUS inclusions. In the present study, we examined how DSBs effect FUS phosphorylation in various primate and mouse cellular models. All cell lines derived from human and non-human primates exhibit N-terminal FUS phosphorylation following calicheamicin gamma 1 (CLM) induced DSBs. In contrast, we were unable to detect FUS phosphorylation in mouse-derived primary neurons or immortalized cell lines regardless of CLM treatment, duration, or concentration. Despite DNA damage induced by CLM treatment, we find that mouse cells do not phosphorylate FUS, likely due to reduced levels and activity of DNA-PK compared to human cells. Taken together, our work reveals that mouse-derived cellular models regulate FUS in an anomalous manner compared to primate cells. This raises the possibility that mouse models may not fully recapitulate the pathogenic cascades that lead to FTLD with FUS pathology.