Oncotarget

Research Papers:

Tetratricopeptide repeat domain 3 overexpression tends to form aggregates and inhibit ubiquitination and degradation of DNA polymerase γ

Yueqing Gong, Xiaolan Wang, Xuan Shang, Sheng Ping Xiao, Wanjie Li, Yu Shang and Fei Dou _

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Oncotarget. 2017; 8:106475-106485. https://doi.org/10.18632/oncotarget.22476

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Abstract

Yueqing Gong1,2,3, Xiaolan Wang1,2,3, Xuan Shang1,2,3, Sheng Ping Xiao1,2,3, Wanjie Li2, Yu Shang2 and Fei Dou1,2,3

1State Key Laboratory of Cognitive Neuroscience and Learning and IDG, McGovern Institute for Brain Research, College of Life Sciences, Beijing Normal University, Beijing, China

2Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing, China

3Center for Collaboration and Innovation in Brain and Learning Sciences, Beijing Normal University, Beijing, China

Correspondence to:

Fei Dou, email: [email protected]

Keywords: TTC3; POLG; ubiquitination; proteostasis; mitochondrion

Received: May 17, 2017     Accepted: October 28, 2017     Published: November 17, 2017

ABSTRACT

Tetratricopeptide repeat (TPR) domain 3 (TTC3) is a protein that contains canonical RING finger and TPR motifs. It is encoded by the TTC3 gene located in the Down syndrome critical region (DSCR). In this study, we used a yeast two-hybrid assay to identify several proteins that physically interact with TTC3, including heat shock proteins and DNA polymerase γ (POLG). When TTC3 was overexpressed in mammalian cells, the ubiquitination of POLG was inhibited and its degradation slowed. High TTC3 protein expression led to the development of intracellular TTC3 aggregates, which also contained POLG. Co-expression with Hsp70 or placing the TTC3 gene under control of an inducible promoter alleviated the aggregation and facilitated POLG degradation. As a result of POLG’s effects on aging processes, we propose that a copy number variant of the TTC3 may contribute to Down syndrome pathogenesis.


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