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Assessment of Global DNA Double-Strand End Resection using BrdU-DNA Labeling coupled with Cell Cycle Discrimination Imaging
Published on: April 28, 2021
Targeting Mouse Double Minute 2: Current Concepts in DNA Damage Repair and Therapeutic Approaches in Cancer
Wen Li1, Xinhao Peng1,2, Jinyi Lang1,2
1Cancer Clinical Research Center & Integrative Cancer Center, Sichuan Cancer Hospital & Institute Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
Abstract:
Defects in DNA damage repair may cause genome instability and cancer development. The tumor suppressor gene p53 regulates cell cycle arrest to allow time for DNA repair. The oncoprotein mouse double minute 2 (MDM2) promotes cell survival, proliferation, invasion, and therapeutic resistance in many types of cancer. The major role of MDM2 is to inhibit p53 activity and promote its degradation. In this review, we describe the influence of MDM2 on genomic instability, the role of MDM2 on releasing p53 and binding DNA repair proteins to inhibit repair, and the regulation network of MDM2 including its transcriptional modifications, protein stability, and localization following DNA damage in genome integrity maintenance and in MDM2-p53 axis control. We also discuss p53-dependent and p53 independent oncogenic function of MDM2 and the outcomes of clinical trials that have been used with clinical inhibitors targeting p53-MDM2 to treat certain cancers.
Insights
Defects in DNA repair can lead to cancer. This review details how mouse double minute 2 (MDM2) impacts genomic instability by inhibiting p53 and DNA repair proteins, affecting cancer progression and treatment.
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- DNA damage repair defects are linked to genome instability and cancer.
- The tumor suppressor p53 is crucial for cell cycle arrest and DNA repair.
- The oncoprotein MDM2 inhibits p53 and promotes cancer cell survival and proliferation.
Purpose of the Study:
- To review the influence of MDM2 on genomic instability.
- To elucidate MDM2's role in inhibiting p53 and DNA repair.
- To discuss MDM2's regulatory network and oncogenic functions.
Main Methods:
- Literature review of MDM2's function in DNA damage response.
- Analysis of MDM2's interactions with p53 and DNA repair proteins.
- Examination of MDM2's regulatory network and oncogenic pathways.
Main Results:
- MDM2 significantly contributes to genomic instability by suppressing p53 and DNA repair.
- MDM2 regulates its own stability, localization, and transcriptional modifications post-DNA damage.
- MDM2 exhibits both p53-dependent and independent oncogenic functions.
Conclusions:
- MDM2 plays a critical role in maintaining genome integrity and cancer development.
- Targeting the MDM2-p53 axis offers a promising therapeutic strategy for various cancers.
- Clinical trials investigating MDM2 inhibitors show potential for cancer treatment.
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