{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n DCAF15 is a substrate‐receptor component of the CRL4 E3 ubiquitin ligase complex that plays a central role in mediating targeted protein degradation. In the presence of aryl sulfonamide compounds such as indisulam, tasisulam, E7820, and related agents, DCAF15 facilitates the recruitment of specific splicing regulatory proteins—including RBM39 and its paralog RBM23—thereby promoting their polyubiquitination and proteasomal degradation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": " Structural and kinetic studies have revealed that these compounds act as “molecular glues” by binding to a shallow pocket on DCAF15, thus enhancing its low‐affinity interactions with substrate proteins and ensuring efficient neo‐substrate recruitment.\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond splicing factor degradation, DCAF15 is implicated in the regulation of alternative pre‐mRNA splicing events that influence the expression of critical oncogenic isoforms. For example, through the DCAF15/RBM39 pathway, the splicing of the minor KRAS4A isoform is modulated—a process that appears essential for the development of mutant KRAS-driven tumors."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In addition, DCAF15 has been shown to recognize other substrates such as ZEB1 and ARNT, thereby impacting processes like epithelial–mesenchymal transition and cellular adaptation to hypoxia."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": " Expression levels of DCAF15 correlate with cellular sensitivity to sulfonamide-mediated degradation, underscoring its potential role as a predictive biomarker for therapeutic response in various cancers."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, mapping of critical residues within DCAF15 has provided insights into resistance mechanisms, as mutations in key amino acids (for example, Q232 and D475) can disrupt substrate recruitment and impair drug efficacy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Collectively, these findings establish DCAF15 not only as a pivotal mediator of drug‐induced splicing perturbations and tumor suppression, but also as an attractive target for the development of next-generation protein degraders and novel cancer therapeutics."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ting Han, Maria Goralski, Nicholas Gaskill, et al. 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