DNA damage response revisited: the p53 family and its regulators provide endless cancer therapy opportunities

作者全名："Abuetabh, Yasser; Wu, H. Helena; Chai, Chengsen; Al Yousef, Habib; Persad, Sujata; Sergi, Consolato M.; Leng, Roger"

作者地址："[Abuetabh, Yasser; Wu, H. Helena; Chai, Chengsen; Al Yousef, Habib; Leng, Roger] Univ Alberta, Dept Lab Med & Pathol, Heritage Med Res Ctr 370, Edmonton, AB T6G 2S2, Canada; [Persad, Sujata] Univ Alberta, Dept Pediat, Edmonton, AB T6G 2E1, Canada; [Sergi, Consolato M.] Univ Ottawa, Childrens Hosp Eastern Ontario CHEO, Div Anat Pathol, Ottawa, ON K1H 8L1, Canada; [Chai, Chengsen] Chongqing Med Univ, Coll Lab Med, Chongqing 400016, Peoples R China"

通信作者："Leng, R (通讯作者)，Univ Alberta, Dept Lab Med & Pathol, Heritage Med Res Ctr 370, Edmonton, AB T6G 2S2, Canada."

来源：EXPERIMENTAL AND MOLECULAR MEDICINE

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:000864996000001

JCR分区：Q1

影响因子：12.8

年份：2022

卷号：54

期号：10

开始页：1658

结束页：1669

文献类型：Review

关键词：　

摘要："Cancer therapy: Responses to DNA damage The tumor suppressor protein p53 is at the center of a network of cellular proteins that coordinate responses to DNA damage, and a deeper understanding of this network could reveal new targets for cancer therapy. Commonly called the 'guardian of the genome', p53 helps determine whether cells initiate repairs or self-destruct in response to genomic disruption. Mutations affecting p53 play a critical role in determining tumor response to therapy. Researchers led by Roger Leng at the University of Alberta, Edmonton, Canada, have reviewed the various proteins and pathways that interact with p53, and thus inform its 'decision-making' process. The development of drugs that affect p53 directly has proven a huge challenge, but these interacting proteins and pathways could offer therapeutic targets. The authors highlight vulnerabilities that could render tumors more susceptible to radiation or chemotherapy. Antitumor therapeutic strategies that fundamentally rely on the induction of DNA damage to eradicate and inhibit the growth of cancer cells are integral approaches to cancer therapy. Although DNA-damaging therapies advance the battle with cancer, resistance, and recurrence following treatment are common. Thus, searching for vulnerabilities that facilitate the action of DNA-damaging agents by sensitizing cancer cells is an active research area. Therefore, it is crucial to decipher the detailed molecular events involved in DNA damage responses (DDRs) to DNA-damaging agents in cancer. The tumor suppressor p53 is active at the hub of the DDR. Researchers have identified an increasing number of genes regulated by p53 transcriptional functions that have been shown to be critical direct or indirect mediators of cell fate, cell cycle regulation, and DNA repair. Posttranslational modifications (PTMs) primarily orchestrate and direct the activity of p53 in response to DNA damage. Many molecules mediating PTMs on p53 have been identified. The anticancer potential realized by targeting these molecules has been shown through experiments and clinical trials to sensitize cancer cells to DNA-damaging agents. This review briefly acknowledges the complexity of DDR pathways/networks. We specifically focus on p53 regulators, protein kinases, and E3/E4 ubiquitin ligases and their anticancer potential."

基金机构：Canadian Institutes of Health Research (CIHR); Natural Sciences and Engineering Research Council of Canada (NSERC); Saudi Arabia Ministry of Education scholarship; Alberta Graduate Excellence Scholarship

基金资助正文：This work was supported by grants from the Canadian Institutes of Health Research (CIHR) and The Natural Sciences and Engineering Research Council of Canada (NSERC) to R.L.; Y.A. was supported by a Saudi Arabia Ministry of Education scholarship and an Alberta Graduate Excellence Scholarship.