Inhibition of SNW 1 association with spliceosomal proteins promotes apoptosis in breast cancer cells

Chanda

Molecular and Cellular Biology

2019

The nuclear factor kappa B (NF-κB) family of transcription factors plays a central role in coordinating the expression of genes that control inflammation, immune responses, cell proliferation, and a variety of other biological processes. In an attempt to identify novel regulators of this pathway, we performed whole-genome RNA interference (RNAi) screens in physiologically relevant human macrophages in response to lipopolysaccharide and tumor necrosis factor alpha (TNF-α). The top hit was SNW1, a splicing factor and transcriptional coactivator. SNW1 does not regulate the cytoplasmic components of the NF-κB pathway but complexes with the NF-κB heterodimer in the nucleus for transcriptional activation. We show that SNW1 detaches from its splicing complex (formed with SNRNP200 and SNRNP220) upon NF-κB activation and binds to NF-κB’s transcriptional elongation partner p-TEFb. We also show that SNW1 is indispensable for the transcriptional elongation of NF-κB target genes such as the interleukin 8 (IL-8) and TNF genes. SNW1 is a unique protein previously shown to be involved in both splicing and transcription, and in this case, its role involves binding to the NF-κB–p-TEFb complex to facilitate transcriptional elongation of some NF-κB target genes.

Section: Resultsmentioning

confidence: 99%

SNW1, a Novel Transcriptional Regulator of the NF-κB Pathway

Chanda

Molecular and Cellular Biology

2019

Fertility and Sterility

“…Four out of the five genes identified in the fibroid number analyses ( SAP130, PLXNA4, IPMK , and SNW1 ) have been previously associated with cancer susceptibility or tumor growth (43–46). While the fifth gene ( PSMD6 ) was previously associated with delay in DNA repair when depleted (47).…”

Section: Discussionmentioning

confidence: 99%

Admixture mapping of uterine fibroid size and number in African American women

Bray

Edwards

Wellons

et al. 2017

Objective To evaluate the relationship between genetic ancestry and uterine fibroid characteristics. Design Cross-sectional study. Setting Not applicable. Patient(s) A total of six hundred and nine African American (AA) participants with image- or surgery-confirmed fibroids in the biorepository at Vanderbilt University (BioVU) electronic health record biorepository and the Coronary Artery Risk Development in Young Adults (CARDIA) studies were included. Intervention(s) None Main outcome Measure(s) Outcome measures include fibroid number (single vs multiple), volume of largest fibroid, and largest fibroid dimension of all fibroid measurements. Result(s) Global ancestry meta-analyses revealed a significant inverse association between percentage of European ancestry and risk of multiple fibroids (odds ratio [OR]: 0.78; 95% confidence interval [CI]: 0.66, 0.93; p = 6.05×10−3). Local ancestry meta-analyses revealed five suggestive (p<4.80×10−3) admixture mapping peaks in 2q14.3-2q21.1, 3p14.2-3p14.1, 7q32.2-7q33, 10q21.1, 14q24.2-14q24.3, for number of fibroids and one suggestive admixture mapping peak (p<1.97×10−3) in 10q24.1-10q24.32 for volume of largest fibroid. Single variant association meta-analyses of the strongest associated region from admixture mapping of fibroid number (10q21.1) revealed a strong association at (single nucleotide polymorphism) SNP variant rs12219990 (OR: 0.41; 95% CI: 0.28, 0.60; p = 3.82×10−6) that was significant after correction for multiple testing. Conclusion(s) Increasing African ancestry is associated with multiple fibroids but not fibroid size. Local ancestry analyses identified several novel genomic regions not previously associated with fibroid number and increasing volume. Future studies are needed to explore the genetic impact that ancestry plays into the development of fibroid characteristics.

“…INTS10 is part of the integrator complex, a complex of proteins that is mainly involved in the transcription of small nuclear RNAs, but has also been linked to transcriptional pausing [21] and has not been linked to cancer previously. The importance of splicing events for tumor cell viability is in line with the enhanced cytotoxicity that has been observed when mRNA splicing was inhibited in cancer cells [36,37]. PRPF8 , one of the key proteins in the spliceosome, is located on the same TP53 -associated deletion as POLR2A .…”

Section: Discussionmentioning

confidence: 99%

Somatic Mutation Patterns in Hemizygous Genomic Regions Unveil Purifying Selection during Tumor Evolution

2016

Identification of cancer driver genes using somatic mutation patterns indicative of positive selection has become a major goal in cancer genomics. However, cancer cells additionally depend on a large number of genes involved in basic cellular processes. While such genes should in theory be subject to strong purifying (negative) selection against damaging somatic mutations, these patterns have been elusive and purifying selection remains inadequately explored in cancer. Here, we hypothesized that purifying selection should be evident in hemizygous genomic regions, where damaging mutations cannot be compensated for by healthy alleles. Using a 7,781-sample pan-cancer dataset, we first confirmed this in POLR2A, an essential gene where hemizygous deletions are known to confer elevated sensitivity to pharmacological suppression. We next used this principle to identify several genes and pathways that show patterns indicative of purifying selection to avoid deleterious mutations. These include the POLR2A interacting protein INTS10 as well as genes involved in mRNA splicing, nonsense-mediated mRNA decay and other RNA processing pathways. Many of these genes belong to large protein complexes, and strong overlaps were observed with recent functional screens for gene essentiality in human cells. Our analysis supports that purifying selection acts to preserve the remaining function of many hemizygously deleted essential genes in tumors, indicating vulnerabilities that might be exploited by future therapeutic strategies.