Tumor-specific mutation induced cytoplasm-localized ARID1B regulates RNA metabolism

AT-rich interaction domain 1B (ARID1B), a mammalian SWI/SNF (also termed BAF) chromatin remodeling complex component, is frequently inactivated in several cancer types. Previous studies from our laboratory have revealed a possible cytoplasmic oncogenic gain-of-function of mutant ARID1B in pancreatic and breast cancers. Tumor-specific mutations located within the region encoding the nuclear localization signal (NLS) of ARID1B results in its sequestration within the cytoplasm. Further, aberrant cytoplasmic localization induces the activation of ERK and Wnt/β-catenin signaling, resulting in potentiation of tumorigenic properties. However, additional perturbations emanating from this aberrant localization have not been explored. Here, we performed in-silico analysis of the cytoplasm-localized ARID1B (cARID1B) interactome and surprisingly identified RNA metabolism as an enriched pathway. We further confirm the interaction of cARID1B with Up-frameshift protein 1 (UPF1), the master regulator of Nonsense-mediated mRNA decay (NMD). Our studies also reveal that cARID1B interacts with additional core processing body (P body) components, including the Enhancer of mRNA-decapping protein 4 (EDC4) and mRNA-decapping enzyme 1A (DCP1A). Both P bodies and NMD are known critical regulators of RNA metabolism. Furthermore, possible activity of cARID1B in regulating NMD was validated based on reporter assays, providing support to cARID1B’s predicted role in regulating mRNA stability. Additional studies revealed perturbations in P-body size and number in the presence of cARID1B. These results appear to suggest a possible functional role of cARID1B in regulating cytoplasmic RNA metabolism, revealing a new paradigm for aberrant tumor-specific SWI/SNF function.

Ms. Mudodi Devaunshi Sadanand, is pursuing her Ph.D. in Molecular Oncology under the guidance of Dr. M.D. Bashyam at CDFD, Hyderabad, India. As a research scholar, she has gained experience in using molecular biology and protein biochemistry-based approaches in cell biology. She has made presentations at the India|EMBO Lecture Course held at the National Centre for Cell Science, Pune, India (2025) and the Hy-Sci 2024 held at IIT Hyderabad, India. She also attended the 42nd Indian Association of Cancer Research conference held at ACTREC, Navi Mumbai, India (2023). She look forward to engaging in substantive discussions at the conference.