ALKBH6 is a Fe(2+)/2-oxoglutarate-dependent dioxygenase that functions as a nucleotide demethylase with specialized substrate preferences 1. It catalyzes oxidative demethylation of nucleic acids, specifically demethylating N-7-methyl-GMP and N-1-methyl-adenosine monophosphate in a phosphate-dependent manner 2. ALKBH6 preferentially binds single-stranded DNA and RNA over double-stranded nucleic acids through unique Flip domains that discriminate against dsDNA and flip methylated lesions 3. The enzyme localizes to both cytoplasm and nucleus and participates in nucleic acid damage repair pathways 3. Clinically, ALKBH6 maintains genomic stability in pancreatic cancer; loss of ALKBH6 increases alkylating agent-induced DNA damage and decreases cell survival, while overexpression correlates with improved patient outcomes 4. ALKBH6 is frequently gained in embryonal rhabdomyosarcoma, suggesting a role in this pediatric malignancy 5. Structurally, ALKBH6 interacts with the tumor suppressor transcription repressor ZMYND11, revealing cross-talk between histone modification and nucleic acid modification in epigenetic regulation 36. This ALKBH6-ZMYND11 interaction represents a previously uncharacterized epigenetic mechanism in tumor suppression.