Poster Presentation 25th Lorne Cancer Conference 2013

Not so minor after all. Emerging roles for “minor class” splicing in cancer. (#399)

Benjamin B Williams 1 2 , Karen G Doggett 1 2 , Sebastian Markmiller 2 3 , Yeliz Boglev 2 , Michael Buchert 1 2 , Tracy L Putoczki 1 2 , Qian Du 1 2 , Joan K Heath 1 2
  1. The Walter and Eliza Hall Institute for Medical Research, Parkville, VIC, Australia
  2. Ludwig Institute for Cancer Research, Parkville, Victoria, Australia
  3. Cellular and Molecular Medicine, University of California, San Diego, California, USA

Splicing is a crucial, yet often overlooked step in the regulation of gene expression. Whilst essentially all genes require the predominant “major class” splicing, a second pathway known as “minor class” splicing is required to remove a specific subtype of introns from less than 0.5% of all human genes. Despite this restricted subset of genes, this type of splicing has recently been shown to be especially interesting in the context of human developmental1-2 and gastrointestinal disease3.

An intriguing observation is that splicing of minor class introns occurs more slowly than other introns suggesting that this may be an important regulatory mechanism for this small set of genes. As observed in humans, mis-regulation of this process can have profound implications in both development and homeostasis. Furthermore, a number of genes crucial in human cancer contain minor class introns, indicating that minor class splicing may play a role in the development and/or prevention of certain cancers. These include key targets in the MAPK and PI3K mitogenic pathways, which are mis-regulated in many human malignancies. To investigate this question we have generated a conditional mutant mouse for Rnpc3, a gene required for minor class splicing. This study will build on our initial studies in zebrafish, and our recent observation that RNPC3 is down-regulated in many human colorectal cancers compared to adjacent normal tissue.

To address the effect of Rnpc3 haploinsufficiency on tumourigenesis we have generated Rnpc3 deficient, murine tumour models driven by a range of mitogenic pathways including gp130/Stat3, Wnt, MAPK and PI3K. Through the comparison of these models we aim to identify the key proteins and pathways through which minor class splicing modulates tumourigenesis. In conjunction, we are investigating the homozygous loss of Rnpc3 during and post-development to allow us to better understand the role of minor class splicing in development, homeostasis and cancer.

  1. Edery P, Marcaillou C, Sahbatou M, Labalme A, Chastang J, Touraine R, Tubacher E, Senni F, Bober MB, Nampoothiri S, Jouk PS, Steichen E, Berland S, Toutain A, Wise CA, Sanlaville D, Rousseau F, Clerget-Darpoux F, Leutenegger AL. Association of TALS developmental disorder with defect in minor splicing component U4atac snRNA. Science. 2011 Apr 8;332(6026):240-3.
  2. He H, Liyanarachchi S, Akagi K, Nagy R, Li J, Dietrich RC, Li W, Sebastian N, Wen B, Xin B, Singh J, Yan P, Alder H, Haan E, Wieczorek D, Albrecht B, Puffenberger E, Wang H, Westman JA, Padgett RA, Symer DE, de la Chapelle A. Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD I. Science. 2011 Apr 8;332(6026):238-40.
  3. Hastings ML, Resta N, Traum D, Stella A, Guanti G, Krainer AR. An LKB1 AT-AC intron mutation causes Peutz-Jeghers syndrome via splicing at noncanonical cryptic splice sites.Nat Struct Mol Biol. 2005 Jan;12(1):54-9.