K120R mutation inactivates p53 by creating an aberrant splice site leading to nonsense-mediated mRNA decay

Cited 11 time in scopus
Metadata Downloads
Title
K120R mutation inactivates p53 by creating an aberrant splice site leading to nonsense-mediated mRNA decay
Author(s)
S Y Lee; J H Park; S Jeong; B Y Kim; Yong-Kook Kang; Y Xu; S K Chung
Bibliographic Citation
Oncogene, vol. 38, no. 10, pp. 1597-1610
Publication Year
2019
Abstract
The point mutation that substitutes lysine with arginine at position 120 of human p53 has been characterized as a missense mutation. The K120R mutation renders the p53 protein disabled for acetylation and, as a result, defective for apoptotic function, which provides a mechanistic link between the missense mutation and tumorigenesis. However, we noticed the failures of tumorigenesis in mice with the mutation, and of the related studies to notice that it has arbitrarily reflected in amino acid change through a sequence modification (AGA) of the original tumor mutation (AGG) by codon degeneracy. Unlike this modified version, we also discovered a novel splicing site the original mutation, TP53 c.359A>G, may induce. Using a human induced pluripotent stem cell line that was engineered to be homozygous for the original mutation, we here identified that the accidental splicing site generates a defective transcript variant with a frame-shifted premature termination codon which is subjected to nonsense-mediated mRNA decay. The authentic splicing still occurs but in extremely low amounts. Taken together, this mutation causes depletion of cellular p53 via defective mRNA, suggesting a new link to tumorigenesis.
ISSN
0950-9232
Publisher
Springer-Nature Pub Group
DOI
http://dx.doi.org/10.1038/s41388-018-0542-3
Type
Article
Appears in Collections:
Division of Research on National Challenges > Aging Research Center > 1. Journal Articles
Files in This Item:
  • There are no files associated with this item.


Items in OpenAccess@KRIBB are protected by copyright, with all rights reserved, unless otherwise indicated.