<span class="paragraphSection"><div class="boxTitle">Abstract</div>Nucleotide repeat expansions contribute to a number of neurological disorders. Mutations and augmented expression in fused in sarcoma (FUS) can result in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here we reveal that FUS is an <span style="font-style: italic;">N</span>1- and <span style="font-style: italic;">N</span>⁶-methyladenosine (m¹A- and m⁶A)-binding protein, where the protein interacts with the methylated adenosines in CAG repeat expansion RNA, thereby leading to the protein’s cytoplasmic redistribution in SH-SY5Y cells. We also found that ectopically expressed FUS co-localizes with CAG repeat RNA in the cytosol. This co-localization is diminished upon genetic depletion of m⁶A and m¹A writer proteins (i.e. METTL3 and TRMT61A), pharmacological inhibition of METTL3, and ectopic overexpression of m¹A and m⁶A eraser proteins (i.e. ALKBH3 and FTO). Moreover, binding to methylated CAG repeat RNA renders the ectopically expressed FUS protein less dynamic in cells. Together, our study underscores a critical role for m¹A and m⁶A in enhancing FUS–RNA interaction, which results in aberrant subcellular distribution and attenuated mobility of the protein in cells. These findings unveil a novel mechanism underlying neurodegenerative disorders emanating from elevated expression of FUS and suggest targeting FUS-methylated adenosine interactions as a potential therapeutic strategy for FUS proteinopathy.</span>