FUsed in Sarcoma is a Novel Regulator of Manganese Superoxide Dismutase Gene Transcription

Authors

Sanjit Kumar Dhar, University of KentuckyFollow
Jiayu Zhang, University of KentuckyFollow
Jozsef Gal, University of KentuckyFollow
Yong Xu, University of KentuckyFollow
Lu Miao, University of KentuckyFollow
Bert C. Lynn, University of KentuckyFollow
Haining Zhu, University of KentuckyFollow
Edward J. Kasarskis, University of KentuckyFollow
Daret K. St. Clair, University of KentuckyFollow

Abstract

AIMS: FUsed in sarcoma (FUS) is a multifunctional DNA/RNA-binding protein that possesses diverse roles, such as RNA splicing, RNA transport, DNA repair, translation, and transcription. The network of enzymes and processes regulated by FUS is far from being fully described. In this study, we have focused on the mechanisms of FUS-regulated manganese superoxide dismutase (MnSOD) gene transcription.

RESULTS: Here we demonstrate that FUS is a component of the transcription complex that regulates the expression of MnSOD. Overexpression of FUS increased MnSOD expression in a dose-dependent manner and knockdown of FUS by siRNA led to the inhibition of MnSOD gene transcription. Reporter analyses, chromatin immunoprecipitation assay, electrophoretic mobility shift assay, affinity chromatography, and surface plasmon resonance analyses revealed the far upstream region of MnSOD promoter as an important target of FUS-mediated MnSOD transcription and confirmed that FUS binds to the MnSOD promoter and interacts with specificity protein 1 (Sp1). Importantly, overexpression of familial amyotropic lateral sclerosis (fALS)-linked R521G mutant FUS resulted in a significantly reduced level of MnSOD expression and activity, which is consistent with the decline in MnSOD activity observed in fibroblasts from fALS patients with the R521G mutation. R521G-mutant FUS abrogates MnSOD promoter-binding activity and interaction with Sp1.

INNOVATION AND CONCLUSION: This study identifies FUS as playing a critical role in MnSOD gene transcription and reveals a previously unrecognized relationship between MnSOD and mutant FUS in fALS.

Document Type

Article

Publication Date

3-5-2014

Notes/Citation Information

Published in Antioxidants & Redox Signaling, v. 20, no. 10, p. 1550-1566.

This is a copy of an article published in Antioxidants & Redox Signaling © 2014 [copyright Mary Ann Liebert, Inc.]; Antioxidants & Redox Signaling is available online at: http://online.liebertpub.com/loi/ars

Digital Object Identifier (DOI)

http://dx.doi.org/10.1089/ars.2012.4984

Repository Citation

Dhar, Sanjit Kumar; Zhang, Jiayu; Gal, Jozsef; Xu, Yong; Miao, Lu; Lynn, Bert C.; Zhu, Haining; Kasarskis, Edward J.; and St. Clair, Daret K., "FUsed in Sarcoma is a Novel Regulator of Manganese Superoxide Dismutase Gene Transcription" (2014). Toxicology and Cancer Biology Faculty Publications. 20.
https://uknowledge.uky.edu/toxicology_facpub/20