Base excision repair accessory factors in senescence avoidance and resistance to treatments
Elise Vickridge1,2, Camila C F Faraco1,3,2, Alain Nepveu1,3,4,5
1Goodman Cancer Institute, McGill University, 1160 Pine avenue West, Montreal, Québec H3A 1A3, Canada.
Abstract:
Cancer cells, in which the RAS and PI3K pathways are activated, produce high levels of reactive oxygen species (ROS), which cause oxidative DNA damage and ultimately cellular senescence. This process has been documented in tissue culture, mouse models, and human pre-cancerous lesions. In this context, cellular senescence functions as a tumour suppressor mechanism. Some rare cancer cells, however, manage to adapt to avoid senescence and continue to proliferate. One well-documented mode of adaptation involves increased production of antioxidants often associated with inactivation of the KEAP1 tumour suppressor gene and the resulting upregulation of the NRF2 transcription factor. In this review, we detail an alternative mode of adaptation to oxidative DNA damage induced by ROS: the increased activity of the base excision repair (BER) pathway, achieved through the enhanced expression of BER enzymes and DNA repair accessory factors. These proteins, exemplified here by the CUT domain proteins CUX1, CUX2, and SATB1, stimulate the activity of BER enzymes. The ensued accelerated repair of oxidative DNA damage enables cancer cells to avoid senescence despite high ROS levels. As a by-product of this adaptation, these cancer cells exhibit increased resistance to genotoxic treatments including ionizing radiation, temozolomide, and cisplatin. Moreover, considering the intrinsic error rate associated with DNA repair and translesion synthesis, the elevated number of oxidative DNA lesions caused by high ROS leads to the accumulation of mutations in the cancer cell population, thereby contributing to tumour heterogeneity and eventually to the acquisition of resistance, a major obstacle to clinical treatment.
Insights
Cancer cells adapt to high reactive oxygen species (ROS) by enhancing DNA repair, avoiding senescence. This adaptation increases resistance to genotoxic treatments and promotes tumor heterogeneity.
Area of Science:
- Molecular Biology
- Cancer Research
- DNA Repair Mechanisms
Background:
- Cancer cells with activated RAS and PI3K pathways generate high reactive oxygen species (ROS), leading to oxidative DNA damage and cellular senescence.
- Cellular senescence typically acts as a tumor suppressor mechanism, but some cancer cells evade it.
- Adaptation strategies include antioxidant production (via KEAP1/NRF2) or enhanced DNA repair.
Purpose of the Study:
- To explore an alternative adaptation mechanism in cancer cells: enhanced base excision repair (BER) pathway activity.
- To investigate how increased BER activity allows cancer cells to bypass senescence despite high ROS levels.
- To understand the implications of this adaptation for genotoxic treatment resistance and tumor evolution.
Main Methods:
- Review of existing literature on cancer cell adaptation to oxidative stress.
- Analysis of the role of base excision repair (BER) enzymes and accessory factors in managing ROS-induced DNA damage.
- Examination of proteins like CUX1, CUX2, and SATB1 in stimulating BER activity.
Main Results:
- Cancer cells can adapt to high ROS by upregulating the base excision repair (BER) pathway.
- Enhanced expression of BER enzymes and accessory factors, such as CUT domain proteins, accelerates the repair of oxidative DNA damage.
- This accelerated repair enables cancer cells to avoid senescence and continue proliferating.
- The adaptation confers resistance to genotoxic agents like ionizing radiation, temozolomide, and cisplatin.
- Elevated DNA repair and translesion synthesis contribute to increased mutation rates, driving tumor heterogeneity and acquired resistance.
Conclusions:
- Enhanced base excision repair (BER) is a critical, alternative mechanism for cancer cells to evade senescence induced by ROS.
- This BER-driven adaptation not only promotes cancer cell survival but also contributes to treatment resistance and tumor evolution.
- Targeting BER pathways could offer new therapeutic strategies against cancers exhibiting high oxidative stress.
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