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
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.
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