We previously discovered that ATM, in addition to serving many roles in cell-cycle regulation and DNA damage response, also functions as a key epigenetic regulator in neurons, likely underlying the ataxic symptoms as well as neurodegeneration. ATM indirectly regulates nuclear-cytoplasmic shuttling of HDAC4 (Li et al., 2012), and it directly phosphorylates EZH2, the enzymatic component of the PRC2 complex (Li et al., 2013). Each of these mechanisms contributes to ataxia symptoms in knockout mouse models, because reversal restores behavioral function. ATM also phosphorylates TET1, leading to conversion of 5mC to 5hmC marks, thought to be a key step in DNA demethylation (Jiang et al., 2015). Others have reported an effect on the DNMT1 methyltransferase via ATM phosphorylation of the Rb protein (Shamma et al., 2013). Any or all of these mechanisms could be affected or modulated by domains within a truncated ATM protein.
