Targeting Mouse Double Minute 2: Current Concepts in DNA Damage Repair and Therapeutic Approaches in Cancer

Wen Li; Xinhao Peng; Jinyi Lang; Chuan Xu

doi:10.3389/fphar.2020.00631

Targeting Mouse Double Minute 2: Current Concepts in DNA Damage Repair and Therapeutic Approaches in Cancer

Front Pharmacol. 2020 May 7:11:631. doi: 10.3389/fphar.2020.00631. eCollection 2020.

Authors

Wen Li¹, Xinhao Peng^{1

2}, Jinyi Lang^{1

2}, Chuan Xu¹

Affiliations

¹ Cancer 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.
² Radiation Oncology Key Laboratory of Sichuan Province, 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.

Keywords: DNA damage repair; MDM2; P53; clinical inhibitor; genomic instability.

Publication types

Review