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NOTCH1 modulates activity of DNA-PKcs
Marek Adamowicz1, Fabrizio d'Adda di Fagagna2, Jelena Vermezovic3
1IFOM Foundation - FIRC Institute of Molecular Oncology Foundation, 20139 Milan, Italy; Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RH, UK.
Mutation Research
|February 27, 2018
Summary
NOTCH1 regulates DNA-PKcs activity in DNA repair, affecting its phosphorylation but not overall DNA damage repair or cell survival. This suggests NOTCH1 is a physiological modulator of DNA-PKcs in non-homologous end joining (NHEJ) pathway.
Area of Science:
- Molecular Biology
- Cellular Biology
- Genetics
Background:
- DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is crucial for DNA repair via non-homologous end joining (NHEJ).
- The precise function of DNA-PKcs in NHEJ is not fully understood.
Purpose of the Study:
- To investigate the role of NOTCH1 in modulating DNA-PKcs activity within the NHEJ pathway.
- To elucidate the mechanism by which NOTCH1 influences DNA-PKcs function.
Main Methods:
- Assessing the impact of NOTCH1 on DNA-PKcs autophosphorylation and XRCC4 phosphorylation.
- Evaluating DNA damage repair efficiency and cellular survival in NOTCH1-expressing cells.
- Conducting in vitro kinase assays to determine NOTCH1's effect on DNA-PKcs kinase activity.
Main Results:
- NOTCH1 attenuates DNA-PKcs autophosphorylation and XRCC4 phosphorylation.
- NOTCH1-expressing cells show no significant impairment in DNA repair or survival and remain sensitive to DNA-PKcs inhibitors.
- In vitro assays reveal NOTCH1 does not inhibit DNA-PKcs kinase activity, indicating an alternative mechanism of action.
Conclusions:
- NOTCH1 acts as a physiological regulator of DNA-PKcs.
- NOTCH1's interaction with DNA-PKcs offers a novel approach to understanding the mechanisms of NHEJ DNA repair.
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