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Divide and conquer: nucleotide excision repair battles cancer and ageing
James R Mitchell1, Jan H J Hoeijmakers, Laura J Niedernhofer
1Department of Cell Biology and Genetics, Erasmus University Rotterdam, PO Box 1738, 3000 DR, Rotterdam, The Netherlands.
Abstract:
Protection from cancer and ensured longevity are tightly linked in mammals. One of the fundamental mechanisms contributing to both is the cellular response to DNA damage. The appropriate response is an initial attempt at repair, but if the damage is too extensive or compromises DNA metabolism, a signalling cascade triggers cellular senescence or death. Evidence in mice and humans suggests a division of tasks amongst DNA repair pathways: transcription-coupled repair and interstrand crosslink repair of cytotoxic lesions are predominantly responsible for longevity assurance, whereas excision repair of mutagenic lesions provides protection against cancer. Similarly, the signalling component of the DNA-damage response might contribute unequally to organismal outcomes depending on its set point: an inadequate response to DNA damage sanctions carcinogenesis but might limit local ageing, whereas overzealous signalling provides cancer protection but accelerates ageing.
Insights
Cellular responses to DNA damage are key to cancer protection and longevity. Different DNA repair pathways and signaling responses impact these outcomes, balancing cancer prevention with aging.
Area of Science:
- Genetics
- Molecular Biology
- Cellular Biology
Background:
- Cancer protection and longevity are interconnected in mammals.
- The cellular response to DNA damage is a fundamental mechanism underlying both processes.
- Appropriate DNA damage response involves repair, senescence, or cell death.
Purpose of the Study:
- To investigate the distinct roles of DNA repair pathways in longevity and cancer protection.
- To explore how the signaling component of DNA damage response influences organismal aging and cancer risk.
Main Methods:
- Analysis of evidence from mouse and human studies.
- Comparative examination of different DNA repair pathways (transcription-coupled repair, interstrand crosslink repair, excision repair).
- Assessment of the impact of DNA damage response signaling set points on aging and carcinogenesis.
Main Results:
- Transcription-coupled repair and interstrand crosslink repair are crucial for longevity.
- Excision repair of mutagenic lesions primarily confers cancer protection.
- The set point of DNA damage response signaling influences the trade-off between cancer risk and aging rate.
Conclusions:
- Specific DNA repair pathways have specialized roles in maintaining healthspan and lifespan.
- The balance of DNA damage response signaling is critical for preventing cancer while modulating the aging process.