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APE1 polymorphic variants cause persistent genomic stress and affect cancer cell proliferation
Lisa Lirussi1,2, Giulia Antoniali1, Chiara D'Ambrosio3
1Laboratory of Molecular Biology and DNA Repair, Department of Medical and Biological Sciences, University of Udine, 33100 Udine, Italy.
Oncotarget
|April 7, 2016
Summary
Genetic mutations in Apurinic/apyrimidinic endonuclease 1 (APE1) impair DNA repair, leading to chronic DNA damage response and potential cancer susceptibility. These APE1 variants cause cellular defects without external triggers.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Apurinic/apyrimidinic endonuclease 1 (APE1) is crucial for base excision repair (BER) of endogenous DNA damage.
- Genetic variants of APE1 are linked to diseases, but their functional impact remains unclear.
Purpose of the Study:
- To investigate the molecular and cellular consequences of expressing four non-synonymous APE1 variants in human cells.
- To establish a functional link between APE1 mutations and disease development.
Main Methods:
- Selective expression of four APE1 variants (L104R, R237C, D148E, D283G) in human cells.
- Assessed endonuclease activity, protein-protein interactions (XRCC1, DNA polymerase β), histone H2Ax phosphorylation, and poly(ADP-ribosyl)ated protein levels.
- Utilized shRNA to silence endogenous APE1 for complementation experiments.
Main Results:
- Three APE1 variants (D283G, L104R, R237C) exhibited reduced endonuclease activity and impaired interactions with downstream BER enzymes.
- Expression of these variants led to increased DNA damage response markers (histone H2Ax phosphorylation, PAR proteins) in APE1-silenced cells.
- Observed cellular growth defects, apoptosis, and autophagy, indicating chronic replication stress.
Conclusions:
- Non-synonymous APE1 variants can disrupt BER, causing persistent DNA damage response and cellular dysfunction.
- These findings support the hypothesis that APE1 variants may function as cancer susceptibility alleles.
- Chronic replication stress due to BER defects contributes to disease pathogenesis.
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