Human DBR1 modulates the recycling of snRNPs to affect alternative RNA splicing and contributes to the suppression of cancer development

• Published in: Oncogene 2017-09, Vol.36 (38), p.5382-5391
• Main Authors: Han, B, Park, H K, Ching, T, Panneerselvam, J, Wang, H, Shen, Y, Zhang, J, Li, L, Che, R, Garmire, L, Fei, P
• Format: Article
• Language: English
• Subjects: 13/109; 13/31; 13/89; 14/19; 38/77; 38/91; 59/5; 631/337/1645/1792; 631/67/327; 82/16; 96/2; Alternative Splicing; Apoptosis; Cancer; Carcinogenesis; Cell Biology; Cell Hypoxia - physiology; Cell Line, Tumor; Enzymes; Exon skipping; Exons; Gene expression; Genetic aspects; Health aspects; Human Genetics; Humans; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1 - genetics; Hypoxia-Inducible Factor 1 - metabolism; Hypoxia-inducible factors; Internal Medicine; Introns; Medicine; Medicine & Public Health; Neoplasia; Neoplasms - enzymology; Neoplasms - genetics; Neoplasms - metabolism; Oncogenes; Oncology; Original; original-article; p53 Protein; Ribonucleic acid; Ribonucleoproteins; Ribonucleoproteins, Small Nuclear - genetics; Ribonucleoproteins, Small Nuclear - metabolism; RNA; RNA Nucleotidyltransferases - biosynthesis; RNA Nucleotidyltransferases - genetics; RNA Nucleotidyltransferases - metabolism; RNA processing; RNA Splicing; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumorigenesis; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2017.150

The contribution of RNA processing to tumorigenesis is understudied. Here, we report that the human RNA debranching enzyme (hDBR1), when inappropriately regulated, induces oncogenesis by causing RNA processing defects, for example, splicing defects. We found that wild-type p53 and hypoxia-inducible factor 1 co-regulate hDBR1 expression, and insufficient hDBR1 leads to a higher rate of exon skipping. Transcriptomic sequencing confirmed the effect of hDBR1 on RNA splicing, and metabolite profiling supported the observation that neoplasm is triggered by a decrease in hDBR1 expression both in vitro and in vivo . Most importantly, when modulating the expression of hDBR1, which was found to be generally low in malignant human tissues, higher expression of hDBR1 only affected exon-skipping activity in malignant cells. Together, our findings demonstrate previously unrecognized regulation and functions of hDBR1, with immediate clinical implications regarding the regulation of hDBR1 as an effective strategy for combating human cancer.