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Laser Microirradiation to Study In Vivo Cellular Responses to Simple and Complex DNA Damage
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p53-dependent crosstalk between DNA replication integrity and redox metabolism mediated through a NRF2-PARP1 axis
Gamal Ahmed Elfar1,2, Obed Aning1, Tsz Wai Ngai1
1NUS Department of Pathology, National University of Singapore, Yong Loo Lin School of Medicine, Singapore.
Nucleic Acids Research
|September 24, 2024
Summary
The tumor suppressor p53 limits replication stress by controlling PARP1 activity, preventing genome instability. Loss of p53 or RRM2B activates an NRF2-PARP1 axis, linking redox metabolism to genome integrity.
Area of Science:
- Molecular Biology
- Genomics
- Cancer Research
Background:
- The tumor suppressor p53 is crucial for maintaining genomic stability.
- Mechanisms of p53-mediated genome protection during replication stress are not fully understood.
Purpose of the Study:
- To uncover the role of p53 in curbing replication stress.
- To identify p53-dependent factors involved in genome protection.
- To elucidate the crosstalk between redox metabolism and genome integrity.
Main Methods:
- Investigated p53-dependent factors.
- Analyzed the consequences of p53/RRM2B deficiency.
- Studied the NRF2-PARP1 axis and its regulation by G6PD.
Main Results:
- p53 limits replication stress by inhibiting PARP1 activity and preventing degradation of stalled replication forks.
- RRM2B was identified as a key p53-dependent factor.
- p53/RRM2B deficiency activates NRF2, increasing basal PARylation via G6PD.
- A novel NRF2-PARP1 axis links redox metabolism and genome integrity.
Conclusions:
- Loss of p53 destabilizes the replicating genome through an NRF2-PARP1 axis.
- This pathway represents a novel crosstalk between redox metabolism and genome integrity.
- The findings have broad relevance in cancer and suggest therapeutic opportunities.
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