Aryl Sulfonamides Degrade RBM39 and RBM23 by Recruitment to CRL4-DCAF15

Abstract

Highlights d RBM39 is recruited to DCAF15 by indisulam through its RRM2 domain d DCAF15 mutations in Q232 and D475 prevent indisulamdependent RBM39 recruitment d RBM23 is an indisulam-dependent neo-substrate for CRL4-DCAF15 d Indisulam-related mRNA expression and RNA splicing changes are RBM39 dependent

Aryl Sulfonamides Induce Degradation of Aryl Hydrocarbon Receptor Nuclear Translocator through CRL4DCAF15 E3 Ligase

“…Two consecutive studies using quantitative mass spectrometry have reported that aryl sulfonamide downregulates two specific RBM proteins (RBM23 and RBM39) possessing the conserved α-helical degron motif (Ting et al, 2019). ARNT was not identified as a degradation target of aryl sulfonamide in earlier studies (Han et al, 2017;Ting et al, 2019;Uehara et al, 2017), in contrast to our observation that ARNT levels were decreased in the presence of indisulam and E7820. This discrepancy may be attributed to the relatively slow degradation rate of ARNT.…”

“…For example, IMiDs bridge CRBN and Zn-finger proteins, inducing degradation of a subset of Zn-finger proteins (Kronke et al, 2014;Zhu et al, 2014), while aryl sulfonamides attach DCAF15 to RBM proteins and promote degradation of RBM proteins (Han et al, 2017;Uehara et al, 2017). Two consecutive studies using quantitative mass spectrometry have reported that aryl sulfonamide downregulates two specific RBM proteins (RBM23 and RBM39) possessing the conserved α-helical degron motif (Ting et al, 2019). ARNT was not identified as a degradation target of aryl sulfonamide in earlier studies (Han et al, 2017;Ting et al, 2019;Uehara et al, 2017), in contrast to our observation that ARNT levels were decreased in the presence of indisulam and E7820.…”

“…Aryl sulfonamides, including indisulam and E7820, promote ternary complex formation with DCAF15 and RBM proteins (RBM23 and RBM39), subsequently inducing degradation of RBM23 and RBM39 (Han et al, 2017;Ting et al, 2019;Uehara et al, 2017). The stable interactions observed between ARNT and subunits of CRL4 DCAF15 led us to investigate whether aryl sulfonamides affect the stability of ARNT.…”

“…Aryl sulfonamide is reported to exert anti-cancer activity by inducing G1 cell cycle arrest, leading to cell death (Assi et al, 2018;Owa et al, 1999;Van Kesteren et al, 2002). Several subsequent studies have demonstrated that aryl sulfonamide functions as molecular glue, facilitating ternary complex formation with DCAF15 and RNA-binding proteins (RBM39 and RBM23), thereby inducing their degradation (Han et al, 2017;Ting et al, 2019;Uehara et al, 2017). RBM39 not only regulates global alternative splicing but also acts as a transcriptional coactivator for ERα/β and AP-1 (Jung et al, 2002;Kang et al, 2015;Mai et al, 2016).…”

Arylsulfonamide mediated RBM39 degradation causes aberrant splicing of mitotic kinesins

“…RBM23 -whose second RRM domain (RBM23 RRM2 ) shares near perfect sequence homology with that of RBM39 (RBM39 RRM2 ) -as well as RBM5 were the only other RNA binding protein consistently downregulated (Figure 2A,C). Although RBM23 is a bona fide [17,21] molecular glue substrate of DCAF15/ArSulfs, it was obscured in the volcano plots by number of other significant hits that were likely not DCAF15 neosubstrates. Since global proteomics analyses incorporate a summation of both transcriptional and post-transcriptional effects, we reasoned that removing RBM39-eCLIP enriched targets (dataset previously generated in one of our labs) [23] from those identified in proteomics might provide a clearer picture of potential molecular glue targets.…”