A human-specific switch of alternatively spliced AFMID isoforms contributes to TP53 mutations and tumor recurrence in hepatocellular carcinoma

Lin, K. T., Ma, W. K., Scharner, J., Liu, Y. R., Krainer, A. R. (February 2018) A human-specific switch of alternatively spliced AFMID isoforms contributes to TP53 mutations and tumor recurrence in hepatocellular carcinoma. Genome Res. ISSN 1088-9051

URL: https://www.ncbi.nlm.nih.gov/pubmed/29449409
DOI: 10.1101/gr.227181.117

Abstract

Pre-mRNA splicing can contribute to the switch of cell identity that occurs in carcinogenesis. Here, we analyze a large collection of RNA-seq data sets and report that splicing changes in hepatocyte-specific enzymes, such as AFMID and KHK, are associated with HCC patients' survival and relapse. The switch of AFMID isoforms is an early event in HCC development and is associated with driver mutations in TP53 and ARID1A The switch of AFMID isoforms is human-specific and not detectable in other species, including primates. Finally, we show that overexpression of the full-length AFMID isoform leads to a higher NAD(+) level, lower DNA-damage response, and slower cell growth in HepG2 cells. The integrative analysis uncovered a mechanistic link between splicing switches, de novo NAD(+) biosynthesis, driver mutations, and HCC recurrence.

Item Type: Paper
Subjects: diseases & disorders > cancer > cancer types > liver cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNA splicing
CSHL Authors:
Communities: CSHL labs > Krainer lab
CSHL Cancer Center Program > Gene Regulation and Cell Proliferation
Depositing User: Matt Covey
Date: 15 February 2018
Date Deposited: 07 Mar 2018 17:18
Last Modified: 12 Jun 2018 19:21
PMCID: PMC5848607
Related URLs:
URI: http://repository.cshl.edu/id/eprint/36179

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