Genetic alterations of SUGP1 mimic mutant-SF3B1 splice pattern in lung adenocarcinoma and other cancers

Abstract

Genes involved in 3′-splice site recognition during mRNA splicing constitute an emerging class of oncogenes. SF3B1 is the most frequently mutated splicing factor in cancer, and SF3B1 mutants corrupt branchpoint recognition leading to usage of cryptic 3′-splice sites and subsequent aberrant junctions. For a comprehensive determination of alterations leading to this splicing pattern, we performed a pan-TCGA screening for SF3B1-specific aberrant acceptor usage. While the most of aberrant 3′-splice patterns were explained by SF3B1 mutations, we also detected nine SF3B1 wild-type tumors (including five lung adenocarcinomas). Genomic profile analysis of these tumors identified somatic mutations combined with loss-of-heterozygosity in the splicing factor SUGP1 in five of these cases. Modeling of SUGP1 loss and mutations in cell lines showed that both alterations induced mutant-SF3B1-like aberrant splicing. Our study provides definitive evidence that genetic alterations of SUGP1 genocopy SF3B1 mutations in lung adenocarcinoma and other cancers.

Targeted high throughput mutagenesis of the human spliceosome reveals itsin vivooperating principles

“…In untreated cells, we observed exon skipping (skipped exon, SE) as the most frequent event triggered by the mutations followed by alternative 3’ splice site (A3’SS) use; relatively few introns were impacted [using a difference percent splicing inclusion (ΔPSI) cut-off of ≥ |10%| and FDR > 0.01] (Figure 4E). Among these were changes in 3’ splice site usage in introns of the TMEM14C and ENOSF1 genes, which, strikingly, correspond exactly to changes observed previously in cells harboring SF3B1 cancer mutations or SUGP1 cancer mutations (Figure 4F, G, S4D-F) (Alsafadi et al, 2021; Liu et al, 2020).…”

“…SUGP1 has not yet been visualized in any spliceosome structure, nor are there orthologs in S. cerevisiae or S. pombe. Recent work has identified SUGP1 as a putative tumor suppressor: its loss from the spliceosome was suggested to underlie splicing and oncogenic phenotypes of SF3B1 tumor mutations, and mutations in SUGP1 found in tumors mimic the splicing phenotype of SF3B1 mutant tumors (Alsafadi et al, 2021; Liu et al, 2020; Zhang et al, 2019).…”

“…We mapped hypersensitive mutants to U2 snRNP components, but also to factors that act as late as the second chemical step, after SF3b has dissociated. Strikingly, we obtained resistance mutants in SUGP1, a spliceosomal G-patch protein of unknown function that lacks orthologs in yeast and is also a newly proposed tumor suppressor whose loss underpins the splicing changes induced by cancer-associated SF3B1 mutations (Alsafadi et al, 2021; Liu et al, 2020; Zhang et al, 2019). Our resistance mutations in SUGP1 map in or adjacent to its G-patch motif and modulate splicing changes triggered by PB.…”

Quantitative Proteomic Analysis of Zearalenone Exposure on Uterine Development in Weaned Gilts

“…SUGP1 is an essential gene for coding splicing proteins [ 65 ]. Alsafadi et al [ 66 ] reported that SUGP1 loss and mutations induced abnormal splicing of SF3B1 (core subunit of spliceosome component) in lung adenocarcinoma. In the present study, increased CKM, MME, and MPO, and decreased ALDH1A2, CHGB, and SUGP1 might be related to energy metabolism, oxidative stress, proliferation or apoptosis, immune reaction and various adverse effects induced by ZEA.…”

Chemokine Receptor 1 and its associated immune pathway are downregulated in SF3B1MT blood and non-blood cancers

“…NALM and K562), as well as non-blood transformed cell lines (e.g. HeLa and HEK293 cells) (Darman et al 2015; Alsafadi et al 2016; Mupo et al 2017; Hacken et al 2018; Paolella et al 2017; Saez et al 2017; Lee et al 2018; Yin et al 2019; Alsafadi et al 2021). In our study, we sought to determine the specific role of mutant SF3B1 itself and thus examined it in a non-blood/non-cancer cell type.…”