In contrast, mutant ATXN3 (mATXN3) abrogates PNKP activity to induce DNA strand breaks and activate the DDR-ATM→p53 pathway, as observed in spinocerebellar ataxia 3 (SCA3; Chatterjee et al., 2015; Gao et al., 2015). Here, ATXN3 is linked to Machado-Joseph disease.