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

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.