Arsenic regulates ALKBH1 abundance and substrate specificity to promote translation and tumorigenicity.

ABSTRACT: The mechanisms that underlie arsenic tumorigenicity remain incompletely understood. Here, we show that arsenic regulates the abundance and the demethylase activity of ALKBH1, which, in turn, promotes arsenic-induced skin tumorigenesis. At the molecular level, knockdown of ALKBH1 in arsenic-exposed keratinocytes increases m⁶A enrichment in mRNA, and ALKBH1 demethylates m⁶A in vitro in an arsenic-dependent manner. Arsenic binds to the ALKBH1 protein at cysteine residues to regulate the m⁶A RNA demethylase activity of ALKBH1. m⁶A-immunoprecipitation (IP)-sequencing demonstrates that ALKBH1 regulates m⁶A demethylation on the NR2C2 transcript to inhibit NR2C2 protein translation in a YTHDF1-dependent manner. Functionally, knockdown of ALKBH

SUBMITTER: Wilkinson E 

PROVIDER: S-EPMC12696649 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature