Ataxin-3, DNA damage repair, and SCA3 cerebellar degeneration: on the path to parsimony?

Jacqueline M Ward,Albert R La Spada,Christopher E Pearson

doi:10.1371/journal.pgen.1004937

Abstract

Ataxin-3, DNA damage repair, and SCA3 cerebellar degeneration: on the path to parsimony?

Highlights

While some very basic functions of ataxin-3 have been established, these advances have yielded nonintersecting lines of investigation and have not provided an underlying mechanism for Spinocerebellar ataxia type 3 (SCA3) disease pathogenesis. In this issue of PLOS Genetics, two complementary papers establish a key function of ataxin-3 through its interaction with the DNA end-processing enzyme polynucleotide kinase 30-phosphatase (PNKP) and reveal how this interplay contributes to SCA3 pathogenesis [6,7]
Chatterjee et al show that ataxin-3 is a robust interactor with PNKP and promotes PNKP’s phosphatase and DNA repair activities (Fig. 1)
Gao et al demonstrate a dramatic increase in DNA damage in mutant ataxin-3 cells, SCA3 mouse brain, and brain sections from SCA3 patients, corroborating results observed in the Chatterjee et al paper

Summary

Introduction

In this issue of PLOS Genetics, two complementary papers establish a key function of ataxin-3 through its interaction with the DNA end-processing enzyme polynucleotide kinase 30-phosphatase (PNKP) and reveal how this interplay contributes to SCA3 pathogenesis [6,7]. The work by Chatterjee et al uncovers the interaction between ataxin-3 and PKNP in a screen for PNKP-associated proteins. PNKP is an enzyme with key roles in DNA damage repair, maintaining genomic stability of neural cells, and in providing resistance of cancer cells to genotoxic therapeutic agents.

Results

Conclusion