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

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

doi:10.18632/oncotarget.22476

Yueqing Gong, Yu Shang + Show 5 more

Open Access

https://doi.org/10.18632/oncotarget.22476

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Journal: Oncotarget	Publication Date: Nov 17, 2017
Citations: 4	License type: cc-by

Affiliation: Beijing Normal University

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.

Highlights

Human tetratricopeptide repeat (TPR) domain 3 (TTC3) is a gene located on chromosome 21q22.2 within the Down syndrome (DS) critical region (DSCR); it encodes a protein of 2025 amino acid residues [1, 2]
TTC3 proteins interact with POLG and Hsp70
These results suggest that the interaction between TTC3 and POLG is initiated through the N-terminal 1~650 residues, with the N-terminal 1~230 residues being most important

Summary

Introduction

Human tetratricopeptide repeat (TPR) domain 3 (TTC3) is a gene located on chromosome 21q22.2 within the Down syndrome (DS) critical region (DSCR); it encodes a protein of 2025 amino acid residues [1, 2]. DSCR is a region covering 21q11.2 and 21q22.1–22.3, which are thought to be associated with most DS features [3,4,5]. Northern blot analyses have shown that TTC3 expression is regulated, to some extent, in a tissue-specific manner [1, 2, 6]. Further research has shown that TTC3 expression is developmentally regulated during human and mouse embryogenesis [7, 8]. At the earliest stages of development, TTC3 expression is ubiquitous. It becomes restricted to the nervous system

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