DNA-PKcs mutations in dogs and horses: allele frequency and association with neoplasia.
Abstract: Previously, spontaneous genetic immunodeficiencies in mice, Arabian foals, and recently in Jack Russell terriers have been ascribed to defects in DNA-PKcs (catalytic subunit of the DNA dependent protein kinase) expression. In severe combined immunodeficiency (SCID) foals, a 5 bp deletion at codon 9480 results in a frameshift and a 967 amino acid deletion from the C terminus (including the entire PI3 kinase domain) and an unstable mutant protein. In SCID mice, a single base pair mutation results in a premature stop codon and deletion of 83 amino acids; as in SCID foals, the mutant protein is unstable. Here, we define the mutation within the canine DNA-PKcs gene that results in SCID. In this case, a point mutation results in a stop codon at nucleotide 10,828 and premature termination at a position 517 amino acids before the normal C terminus resulting in a functionally null allele. Thus, this is the third documentation of a spontaneous germline mutation in the C terminus of DNA-PKcs. Emerging data implicate DNA repair factors as potential tumor suppressors. Here, we have ascertained the carrier frequency of the defective DNA-PKcs genes in Arabian horses and in Jack Russell terriers. Our data indicate (in good agreement with a previous report) that the carrier frequency of the equine SCID allele is approximately 8%; in contrast, the carrier frequency of the canine SCID allele is less than 1.1%. We also assessed the frequency of the equine SCID allele in a series of 295 tumors from Arabian horses. We find a statistically significant correlation between the development of a virally induced tumor (sarcoid) and heterozygosity for the equine SCID allele. These data provide further support for an emerging consensus: that DNA-PK may normally act as a tumor suppressor through its caretaker role in maintaining chromosomal stability.
Publication Date: 2002-02-28 PubMed ID: 11867233DOI: 10.1016/s0378-1119(01)00880-0Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
- Research Support
- U.S. Gov't
- P.H.S.
Summary
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The research focuses on mutational defects in DNA-PKcs gene, found in Arabian horses and Jack Russell Terriers, which result in severe combined immunodeficiency (SCID), and proposes a potential correlation between these mutations and the development of certain tumors in these animals.
Mutations in the DNA-PKcs Gene
- DNA-PKcs, also known as the catalytic subunit of the DNA dependent protein kinase, is of particular interest due to its essential role in non-homologous end joining (NHEJ), a process vital for repairing double-strand breaks in DNA.
- The researchers have identified the mutation within the canine DNA-PKcs gene that results in SCID, in this case, it is a point mutation leading to the occurrence of a stop codon at nucleotide 10,828. This results in the premature termination of protein synthesis at a position 517 amino acids before the normal C terminus, creating a functionally null allele.
- The mutation in SCID horses, distinctively, is a 5 base pair deletion at codon 9480 that leads to a frameshift and a deletion of 967 amino acids from the C terminus. This includes the entire PI3 kinase domain and results in an unstable mutant protein.
Frequency of Mutations and Association with Neoplasia
- The researchers have also evaluated the carrier frequency of defective DNA-PKcs genes in Arabian horses and Jack Russell terriers. The findings indicate approximately 8% carrier frequency of the SCID allele in Arabian horses, whereas in Jack Russell terriers, the carrier frequency of the SCID allele is found to be less than 1.1%.
- The team further studied the frequency of the equine SCID allele in a sample of 295 tumors from Arabian horses, unearthing a significant statistical correlation between the development of a specific type of virally induced tumor (sarcoid) and the presence of the equine SCID allele.
- These findings therefore propose DNA-PKcs as a potential tumor suppressor, asserting that its primary role might maintain chromosomal stability, hence preventing the development of tumors. This discovery can contribute to the broader understanding of the role of DNA repair factors in cancer biology.
Cite This Article
APA
Ding Q, Bramble L, Yuzbasiyan-Gurkan V, Bell T, Meek K.
(2002).
DNA-PKcs mutations in dogs and horses: allele frequency and association with neoplasia.
Gene, 283(1-2), 263-269.
https://doi.org/10.1016/s0378-1119(01)00880-0 Publication
Researcher Affiliations
- College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA.
MeSH Terms
- Amino Acid Sequence
- Animals
- Base Sequence
- Catalytic Domain / genetics
- Codon, Nonsense
- DNA Mutational Analysis
- DNA, Complementary / chemistry
- DNA, Complementary / genetics
- DNA, Neoplasm / genetics
- DNA-Activated Protein Kinase
- DNA-Binding Proteins
- Dogs
- Gene Frequency
- Genotype
- Heterozygote
- Horses
- Molecular Sequence Data
- Mutation
- Neoplasms / enzymology
- Neoplasms / genetics
- Neoplasms / pathology
- Point Mutation
- Protein Serine-Threonine Kinases / genetics
Grant Funding
- R24 RR016537 / NCRR NIH HHS
- AI32600 / NIAID NIH HHS
- AI42938 / NIAID NIH HHS
Citations
This article has been cited 15 times.- Matsumoto Y, Asa ADDC, Modak C, Shimada M. DNA-Dependent Protein Kinase Catalytic Subunit: The Sensor for DNA Double-Strand Breaks Structurally and Functionally Related to Ataxia Telangiectasia Mutated. Genes (Basel) 2021 Jul 27;12(8).
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