TRIM21-driven K63-linked ubiquitination of RBM38c, as a novel interactor of BECN1, contributes to DNA damage-induced autophagy

Autophagy is essential in DNA damage response by limiting damage, but its responsive activation remains unclear. RBM38 (RBM38a), an RNA-binding protein, regulates mRNA metabolism and plays a key role in controlling cell cycle progression, senescence, and Cancer. In this study, we uncovered a novel primate-specific isoform, RBM38c, with 32 extra Amino acids from exon 2, which imparts a distinct capacity to promote Autophagy upon DNA damage. TP53 increases RBM38c expression upon DNA damage, while TRIM21 facilitates its K63-linked ubiquitination at lysine (K) 35. Activated RBM38c enhances its interaction with BECN1, promoting the formation of the ATG14-containing PtdIns3K-C1 complex and thus Autophagy initiation. A K35R mutation or TRIM21 deficiency impairs RBM38c ubiquitination, preventing Autophagy activation upon DNA damage. Moreover, RBM38c-driven Autophagy protects cells from DNA damage-induced Apoptosis and promotes survival, with this beneficial effect susceptible to suppression by the Autophagy inhibitor 3-methyladenine. Consequently, depleting RBM38c enhances the efficacy of DNA-damaging drugs by impairing Autophagy and increasing DNA damage. Clinical lung Cancer samples show a positive correlation between RBM38c expression and LC3 expression, and this correlation is linked to chemotherapy resistance. Together, our study reveals a novel mechanism for DNA damage-induced Autophagy, involving K63-linked ubiquitination of RBM38c as a critical interactor with BECN1.