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Published on: April 28, 2021
CUT Domain Proteins in DNA Repair and Cancer
Zubaidah M Ramdzan1, Elise Vickridge1, Camila C F Faraco1,2
1Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Montreal, QC H3A 1A3, Canada.
Abstract:
Recent studies revealed that CUT domains function as accessory factors that accelerate DNA repair by stimulating the enzymatic activities of the base excision repair enzymes OGG1, APE1, and DNA pol β. Strikingly, the role of CUT domain proteins in DNA repair is exploited by cancer cells to facilitate their survival. Cancer cells in which the RAS pathway is activated produce an excess of reactive oxygen species (ROS) which, if not counterbalanced by increased production of antioxidants, causes sustained oxidative DNA damage and, ultimately, cell senescence. These cancer cells can adapt by increasing their capacity to repair oxidative DNA damage in part through elevated expression of CUT domain proteins such as CUX1, CUX2, or SATB1. In particular, CUX1 overexpression was shown to cooperate with RAS in the formation of mammary and lung tumors in mice. Conversely, knockdown of CUX1, CUX2, or SATB1 was found to be synthetic lethal in cancer cells exhibiting high ROS levels as a consequence of activating mutations in KRAS, HRAS, BRAF, or EGFR. Importantly, as a byproduct of their adaptation, cancer cells that overexpress CUT domain proteins exhibit increased resistance to genotoxic treatments such as ionizing radiation, temozolomide, and cisplatin.
Insights
CUT domain proteins accelerate DNA repair and are exploited by cancer cells for survival. Inhibiting these proteins is synthetic lethal in cancer cells with high reactive oxygen species (ROS) levels.
Area of Science:
- Molecular Biology
- Cancer Biology
- Genetics
Background:
- CUT domain proteins are accessory factors that enhance DNA repair enzyme activity.
- Cancer cells with activated RAS pathways generate excess reactive oxygen species (ROS), leading to oxidative DNA damage.
- Elevated expression of CUT domain proteins like CUX1, CUX2, and SATB1 aids cancer cell adaptation and survival by boosting DNA repair capacity.
Purpose of the Study:
- To investigate the role of CUT domain proteins in DNA repair and cancer cell survival.
- To explore the synthetic lethality of targeting CUT domain proteins in specific cancer contexts.
- To understand how CUT domain protein overexpression confers resistance to genotoxic treatments.
Main Methods:
- Studied the enzymatic activities of base excision repair enzymes (OGG1, APE1, DNA pol β) with CUT domain proteins.
- Analyzed the effect of RAS pathway activation on ROS levels and DNA damage in cancer cells.
- Investigated the impact of CUX1, CUX2, and SATB1 knockdown on cancer cell viability with high ROS levels.
- Assessed the resistance of CUT domain protein-overexpressing cancer cells to genotoxic agents.
Main Results:
- CUT domains were shown to stimulate the activity of key base excision repair enzymes.
- Overexpression of CUX1 cooperated with RAS in promoting mammary and lung tumor formation in mice.
- Knockdown of CUX1, CUX2, or SATB1 exhibited synthetic lethality in cancer cells with mutations in KRAS, HRAS, BRAF, or EGFR.
- Cancer cells overexpressing CUT domain proteins demonstrated increased resistance to ionizing radiation, temozolomide, and cisplatin.
Conclusions:
- CUT domain proteins play a critical role in DNA repair and cancer cell adaptation.
- Targeting CUT domain proteins represents a potential therapeutic strategy for cancers with high ROS levels and specific mutations.
- Understanding CUT domain protein function provides insights into cancer resistance mechanisms to genotoxic therapies.
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