Li Haixia, Wilkinson Emma, Cui Yan-Hong, Sun Ming, Lu Kenneth, Yang Seungwon, Bissonnette Marc, He Yu-Ying
Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL, USA.
Department of Medicine, Section of Gastroenterology, Hepatology & Nutrition, University of Chicago, Chicago, IL, USA.
Cell Rep. 2025 Jul 22;44(7):115926. doi: 10.1016/j.celrep.2025.115926. Epub 2025 Jun 27.
mA RNA methylation is the most prevalent internal modification in mammalian mRNAs and is involved in many biological processes. METTL16 is a recently identified RNA mA methyltransferase. However, how METTL16 activity is regulated remains poorly understood. Here, we report a previously unrecognized mechanism in regulating METTL16 activity. SSB not only serves as a co-factor for METTL16 in installing mA RNA methylation by enhancing METTL16 binding to RNA but it also is a direct target of METTL16-mediated mA RNA methylation, leading to a positive auto-regulatory loop that promotes mA methylation, SSB expression, and chemoresistance in colorectal cancer cells. Our findings reveal the regulation of METTL16 activity by SSB, providing a basis for the development of future therapeutic strategies that target the METTL16/SSB axis in METTL16-dependent cancers such as colorectal cancer.
N6-甲基腺嘌呤（m6A）RNA甲基化是哺乳动物mRNA中最普遍的内部修饰，参与许多生物学过程。METTL16是最近鉴定出的一种RNA m6A甲基转移酶。然而，METTL16的活性是如何被调控的仍知之甚少。在此，我们报道了一种以前未被认识的调控METTL16活性的机制。单链结合蛋白（SSB）不仅作为METTL16的辅因子，通过增强METTL16与RNA的结合来进行m6A RNA甲基化，而且它也是METTL16介导的m6A RNA甲基化的直接靶点，从而形成一个促进m6A甲基化、SSB表达和大肠癌细胞化疗耐药性的正反馈自调节环。我们的研究结果揭示了SSB对METTL16活性的调控，为未来开发针对METTL16依赖性癌症（如结直肠癌）中METTL16/SSB轴的治疗策略提供了依据。
