Dynamic multilayered control of m6A RNA demethylase activity

• 成果类型: Article
• 署名作者: Jaafar, Carine; Aguiar, Ricardo C. T.
• 署名单位: University of Texas System; University of Texas at San Antonio; US Department of Veterans Affairs; Veterans Health Administration (VHA); Audie L. Murphy Memorial Veterans Hospital
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9962
• DOI: 10.1073/pnas.2317847121
• 发表日期: 2024-11-12
• 关键词: messenger-rna; fat mass; fto gene; binding protein; nuclear-rna; methylation; obesity; alkbh5; cancer; stem

摘要

Similar to DNA and histone, RNA can also be methylated. In its most common form, a N6- methyladenosine (m6A) chemical modification is introduced into nascent messenger ribonucleic acid (mRNA) by a specialized methyltransferase complex and removed by the RNA demethylases, Fat mass and obesity- associated (FTO), and ALKBH5. The fate of m6A- marked mRNA is uniquely diverse, ranging from degradation to stabilization/translation, which has been suggested to be largely dependent on its interaction with the family of YT521- B homology (YTH) domain- containing proteins. Here, we highlight a series of control levers that impinge on the RNA demethylases. We present evidence to indicate that intermediary metabolism and various posttranslation modifications modulate the activity, stability, and the subcellular localization of FTO and ALKBH5, further dispelling the notion that m6A methylation is not a dynamic process. We also discuss how examination of these underappreciated regulatory nodes adds a more nuanced view of the role of FTO and ALKBH5 and should guide their study in cancer and nonmalignant conditions alike.