How carcinogens (or telomere dysfunction) induce genetic instability: associated‐selection model

FEBS Letters

Blagosklonny, Mikhail V¹ 

[1] Medicine Branch, National Cancer Institute, NIH, Bldg. 10, R 12 N 226, Bethesda, MD 20892, USA

关键词: Carcinogen;    Cancer;    Selection;    Genetic instability;    Telomerase;   

DOI  :  10.1016/S0014-5793(01)02894-0

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Carcinogens induce carcinogen-specific genetic instability (defects in DNA repair). According to the ‘direct-selection’ model, defects in DNA repair per se provide an immediate growth advantage. According to the ‘associated-selection’ model, carcinogens merely select for cells with adaptive mutations. Like any mutations, adaptive mutations occur predominantly in genetically unstable cells. The ‘associated-selection’ model predicts that carcinogen-driven selection minimizes cytotoxic but maximizes mutagenic effects of carcinogens. A purely mutagenic (neither cytotoxic, nor cytostatic) environment will favor effective DNA repair, whereas any growth-limiting conditions (telomerase deficiency, anticancer drugs) will select for genetically unstable cells. Genetic instability is a postmark of selective pressure rather than a hallmark of cancer per se. Once selected, genetic instability facilitates the development of resistance to any other growth-limiting conditions. As an example, a putative link between prior exposure to carcinogens and the ability to develop a telomerase-independent growth is discussed.

【 授权许可】

Unknown