Altered endoribonuclease activity of apurinic/apyrimidinic endonuclease 1 variants identified in the human population

Apurinic/apyrimidinic endonuclease 1 (APE1) is the major mammalian enzyme in the DNA base excision repair pathway and cleaves the DNA phosphodiester backbone immediately 5' to abasic sites. APE1 also has 3'-5' DNA exonuclease and 3' DNA phosphodiesterase activities, and regulates...

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Bibliographic Details
Published in:PloS one 2014-03, Vol.9 (3), p.e90837
Main Authors: Kim, Wan Cheol, Ma, Conan, Li, Wai-Ming, Chohan, Manbir, Wilson, 3rd, David M, Lee, Chow H
Format: Article
Language:English
Subjects:
Amino Acid Substitution
Amino acids
Amyotrophic lateral sclerosis
Base Sequence
Biology
Breast cancer
Deoxyribonucleic acid
DNA
DNA - metabolism
DNA repair
DNA-(Apurinic or Apyrimidinic Site) Lyase - genetics
DNA-(Apurinic or Apyrimidinic Site) Lyase - metabolism
Endoribonucleases - genetics
Endoribonucleases - metabolism
Escherichia coli - genetics
Escherichia coli - growth & development
Genes
Glycerol
Human populations
Humans
Kinases
Metabolism
Molecular Sequence Data
Mutagenesis
Mutation
Nucleases
Plasmids
Population
Proteins
Proto-Oncogene Proteins c-myc - genetics
Ribonuclease
RNA
RNA - chemistry
RNA - genetics
RNA - metabolism
Studies
Substrate Specificity
Transcription (Genetics)
Up-Regulation
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Summary:Apurinic/apyrimidinic endonuclease 1 (APE1) is the major mammalian enzyme in the DNA base excision repair pathway and cleaves the DNA phosphodiester backbone immediately 5' to abasic sites. APE1 also has 3'-5' DNA exonuclease and 3' DNA phosphodiesterase activities, and regulates transcription factor DNA binding through its redox regulatory function. The human APE1 has recently been shown to endonucleolytically cleave single-stranded regions of RNA. Towards understanding the biological significance of the endoribonuclease activity of APE1, we examined eight different amino acid substitution variants of APE1 previously identified in the human population. Our study shows that six APE1 variants, D148E, Q51H, I64V, G241R, R237A, and G306A, exhibit a 76-85% reduction in endoribonuclease activity against a specific coding region of the c-myc RNA, yet fully retain the ability to cleave apurinic/apyrimidinic DNA. We found that two APE1 variants, L104R and E126D, exhibit a unique RNase inhibitor-resistant endoribonuclease activity, where the proteins cleave c-myc RNA 3' of specific single-stranded guanosine residues. Expression of L104R and E126D APE1 variants in bacterial Origami cells leads to a 60-80% reduction in colony formation and a 1.5-fold increase in cell doubling time, whereas the other variants, which exhibit diminished endoribonuclease activity, had no effect. These data indicate that two human APE1 variants exhibit a unique endoribonuclease activity, which correlates with their ability to induce cytotoxicity or slow down growth in bacterial cells and supports the notion of their biological functionality.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0090837