RNA-binding proteins of COSMIC importance in cancer
Peter S. Choi, Andrei Thomas-Tikhonenko
Peter S. Choi, Andrei Thomas-Tikhonenko
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Review

RNA-binding proteins of COSMIC importance in cancer

Abstract

Herculean efforts by the Wellcome Sanger Institute, the National Cancer Institute, and the National Human Genome Research Institute to sequence thousands of tumors representing all major cancer types have yielded more than 700 genes that contribute to neoplastic growth when mutated, amplified, or deleted. While some of these genes (now included in the COSMIC Cancer Gene Census) encode proteins previously identified in hypothesis-driven experiments (oncogenic transcription factors, protein kinases, etc.), additional classes of cancer drivers have emerged, perhaps none more surprisingly than RNA-binding proteins (RBPs). Over 40 RBPs responsible for virtually all aspects of RNA metabolism, from synthesis to degradation, are recurrently mutated in cancer, and just over a dozen are considered major cancer drivers. This Review investigates whether and how their RNA-binding activities pertain to their oncogenic functions. Focusing on several well-characterized steps in RNA metabolism, we demonstrate that for virtually all cancer-driving RBPs, RNA processing activities are either abolished (the loss-of-function phenotype) or carried out with low fidelity (the LoFi phenotype). Conceptually, this suggests that in normal cells, RBPs act as gatekeepers maintaining proper RNA metabolism and the “balanced” proteome. From the practical standpoint, at least some LoFi phenotypes create therapeutic vulnerabilities, which are beginning to be exploited in the clinic.

Authors

Peter S. Choi, Andrei Thomas-Tikhonenko

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Figure 2

Roles of COSMIC genes in RNA metabolism pathways.

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Roles of COSMIC genes in RNA metabolism pathways. Listed in boxes are CO...
Listed in boxes are COSMIC Cancer Gene Census genes encoding proteins with RNA-binding activities and classified as tier 1 (“documented activity relevant to cancer”) or tier 2 (“less extensive available evidence”). RBPs further classified as drivers by cBioPortal are highlighted in red text. Although many RBPs function in multiple processes, each RBP was assigned to one primary step in RNA metabolism: transcription, splicing, microRNA biogenesis, nuclear export, folding/turnover, and translation. During transcription, the exact RNA copy of a protein-coding gene is synthesized by RNA polymerase II. It typically contains exon and introns; the latter are being continuously removed during splicing, yielding the mature messenger RNA (mRNA). Some introns (as well as occasional exons) contain short stem-loop structures that are recognized and excised by the Microprocessor complex during early stages of microRNA biogenesis. Both mRNAs and microRNAs are moved to the cytosol via nuclear export. Once in the cytosol, mRNAs undergo translation into proteins by the ribosomes; this process is tightly regulated by various RBPs and also by microRNAs, which bind to complementary sequences, typically in 3′-UTRs of mRNAs, and affect both mRNA stability and recognition of the 5′ cap structures by ribosomes.