Skip to content

Research at St Andrews

Did nucleotides or amino acids drive evolutionary conservation of the WT1 +/-KTS alternative splice?

Research output: Contribution to journalArticlepeer-review

DOI

Author(s)

R C Davies, E Bratt, N D Hastie

School/Research organisations

Abstract

Evolutionary comparisons frequently pinpoint crucial parts of a protein but, even within coding regions, nucleotides can do more than determine amino acid sequence. One highly conserved feature of the Wilms' tumour suppressor gene, WT1, is the potential, following alternative pre-mRNA splicing, to insert three amino acids (KTS) between the third and fourth zinc fingers. The nucleotides at this position simultaneously define amino acids and the alternative splice site. At the protein level this insertion influences DNA binding affinity and specificity, protein-protein interactions and subnuclear localization. Mutations within the +/-KTS splice junction lead to severe urogenital developmental abnormalities such as Frasier syndrome, indicating that the isoform ratio is critical for wild-type function. Using a series of site-directed mutations in both the genomic and cDNA context, the nucleotide-amino acid relationship was investigated. Mutational analysis within the cDNA suggests that the precise amino acids inserted may not be critical, but rather the disruption of the zinc finger structure alone may be sufficient to generate proteins with different in vitro properties. However, analysis within the genomic context suggests that the precise structure of the splice junction is crucial in retaining the balance between the isoforms, and this may account for the high nucleo-tide conservation of this unusual gene structure from fish to mammals.

Close

Details

Original languageEnglish
Pages (from-to)1177-83
Number of pages7
JournalHuman Molecular Genetics
Volume9
Issue number8
DOIs
Publication statusPublished - 1 May 2000

    Research areas

  • Alternative Splicing, Animals, Base Sequence, COS Cells, Cell Line, Conserved Sequence, DNA-Binding Proteins/genetics, Evolution, Molecular, Fishes, Genes, Wilms Tumor, Humans, Kidney Neoplasms/genetics, Mice, RNA Precursors/genetics, Recombinant Proteins/biosynthesis, Sequence Homology, Nucleic Acid, Transcription Factors/genetics, Transfection, WT1 Proteins, Wilms Tumor/genetics, Zinc Fingers

Discover related content
Find related publications, people, projects and more using interactive charts.

View graph of relations

Related by author

  1. Association of human papillomavirus 16 E2 with Rad50-interacting protein 1 enhances viral DNA replication

    Campos-León, K., Wijendra, K., Siddiqa, A., Pentland, I., Feeney, K. M., Knapman, A., Davies, R., Androphy, E. J. & Parish, J. L., Mar 2017, In: Journal of Virology. 91, 5, 18 p., e02305-16.

    Research output: Contribution to journalArticlepeer-review

  2. Stabilization of stalled DNA replication forks by the BRCA2 breast cancer susceptibility protein

    Lomonosov, M., Anand, S., Sangrithi, M., Davies, R. & Venkitaraman, A. R., 15 Dec 2003, In: Genes & Development. 17, 24, p. 3017-22 6 p.

    Research output: Contribution to journalArticlepeer-review

  3. Identification of WTAP, a novel Wilms' tumour 1-associating protein

    Little, N. A., Hastie, N. D. & Davies, R. C., 22 Sep 2000, In: Human Molecular Genetics. 9, 15, p. 2231-9 9 p.

    Research output: Contribution to journalArticlepeer-review

  4. Multiple roles for the Wilms' tumor suppressor, WT1

    Davies, R., Moore, A., Schedl, A., Bratt, E., Miyahawa, K., Ladomery, M., Miles, C., Menke, A., van Heyningen, V. & Hastie, N., 1 Apr 1999, In: Cancer Research. 59, 7 Suppl, p. 1747s-1750s; discussion 1751s

    Research output: Contribution to journalReview articlepeer-review

  5. WT1 interacts with the splicing factor U2AF65 in an isoform-dependent manner and can be incorporated into spliceosomes

    Davies, R. C., Calvio, C., Bratt, E., Larsson, S. H., Lamond, A. I. & Hastie, N. D., 15 Oct 1998, In: Genes & Development. 12, 20, p. 3217-25 9 p.

    Research output: Contribution to journalArticlepeer-review

Related by journal

  1. Human Molecular Genetics (Journal)

    Paul Andrew Reynolds (Reviewer)

    2009 → …

    Activity: Publication peer-review and editorial work typesPeer review of manuscripts

  2. Human Molecular Genetics (Journal)

    Paul Andrew Reynolds (Reviewer)

    2009

    Activity: Publication peer-review and editorial work typesPeer review of manuscripts

Related by journal

  1. A rare missense variant in the ATP2C2 gene is associated with language impairment and related measures

    Martinelli, A., Rice, M., Talcott, J. B., Diaz, R., Smith, S., Hashim Raza, M., Snowling, M. J., Hulme, C., Stein, J., Hayiou-Thomas, M. E., Hawi, Z., Kent, L., Pitt, S. J., Newbury, D. F. & Paracchini, S., 16 Apr 2021, In: Human Molecular Genetics. In press, ddab111.

    Research output: Contribution to journalArticlepeer-review

  2. Lamin A/C dysregulation contributes to cardiac pathology in a mouse model of severe spinal muscular atrophy"

    Šoltić, D., Shorrock, H. K., Allardyce, H., Wilson, E. L., Holt, I., Synowsky, S. A., Shirran, S. L., Parson, S., Gillingwater, T. & Fuller, H., 9 Aug 2019, In: Human Molecular Genetics. Advance Article

    Research output: Contribution to journalArticlepeer-review

  3. The handedness-associated PCSK6 locus spans an intronic promoter regulating novel transcripts

    Shore, R. J., Covill, L., Pettigrew, K. A., Brandler, W. A., Diaz Vazquez, R., Xu, Y., Tello, J., Talcott, J. B., Newbury, D. F., Stein, J., Monaco, A. P. & Paracchini, S., 1 May 2016, In: Human Molecular Genetics. 25, 9, p. 1771-1779 9 p.

    Research output: Contribution to journalArticlepeer-review

  4. The DISC1 promoter: characterization and regulation by FOXP2

    Walker, R. M., Hill, A. E., Newman, A. C., Hamilton, G., Torrance, H. S., Anderson, S. M., Ogawa, F., Derizioti, P., Nicod, J., Vernes, S. C., Fisher, S. E., Thomson, P. A., Porteous, D. J. & Evans, K. L., 1 Jul 2012, In: Human Molecular Genetics. 21, 13, p. 2862-72 11 p.

    Research output: Contribution to journalArticlepeer-review

  5. PCSK6 is associated with handedness in individuals with dyslexia

    Scerri, T. S., Brandler, W. M., Paracchini, S., Morris, A. P., Ring, S. M., Richardson, A. J., Talcott, J. B., Stein, J. & Monaco, A. P., Feb 2011, In: Human Molecular Genetics. 20, 3, p. 608-614 7 p.

    Research output: Contribution to journalArticlepeer-review

ID: 260532791

Top