The biological function and clinical significance of SF3B1 mutations in cancer
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REVIEW
Open Access
The biological function and clinical significance of SF3B1 mutations in cancer Zhixia Zhou1* , Qi Gong2, Yin Wang1, Mengkun Li1, Lu Wang1, Hongfei Ding1 and Peifeng Li1*
Abstract Spliceosome mutations have become the most interesting mutations detected in human cancer in recent years. The spliceosome, a large, dynamic multimegadalton small nuclear ribonucleoprotein composed of small nuclear RNAs associated with proteins, is responsible for removing introns from precursor mRNA (premRNA) and generating mature, spliced mRNAs. SF3B1 is the largest subunit of the spliceosome factor 3b (SF3B) complex, which is a core component of spliceosomes. Recurrent somatic mutations in SF3B1 have been detected in human cancers, including hematological malignancies and solid tumors, and indicated to be related to patient prognosis. This review summarizes the research progress of SF3B1 mutations in cancer, including SF3B1 mutations in the HEAT domain, the multiple roles and aberrant splicing events of SF3B1 mutations in the pathogenesis of tumors, and changes in mutated cancer cells regarding sensitivity to SF3B small-molecule inhibitors. In addition, the potential of SF3B1 or its mutations to serve as biomarkers or therapeutic targets in cancer is discussed. The accumulated knowledge about SF3B1 mutations in cancer provides critical insight into the integral role the SF3B1 protein plays in mRNA splicing and suggests new targets for anticancer therapy. Keywords: SF3B1, Mutation, Cancer, RNA splicing
Background Of the 3.3 billion base pairs of haploid DNA in the human genome, approximately 20,000 protein-coding genes have been identified by the Encyclopedia of DNA Elements (ENCODE) project [1]. However, the number of protein-coding genes is surprisingly low given the proteomic complexity, as the number of protein isoforms expressed from this gene set has been estimated to be at least 5–10-fold higher [2– 4]. The generation of protein diversity is primarily due to the process of precursor mRNA (premRNA) splicing, which is controlled by a complex regulatory system that consists of an enormous number of sequence elements and trans-acting splicing factors; therefore, it is not surprising that the mRNA splicing machinery is susceptible to mutations and that these mutations are implicated in many * Correspondence: [email protected]; [email protected] 1 Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266012, People’s Republic of China Full list of author information is available at the end of the article
human diseases, including cancer [5, 6]. Indeed, genomewide studies have revealed more than 15,000 tumorassociated splice variants in a wide variety of cancers [7, 8]. Recently, the most interesting mutations detected in human cancer were found to target components of the spliceosome involved in the mRNA-splicing process, as indicated by genomic DNA analysis of a variety of human tumors studied through the Cancer Genome Project.
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