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How carcinogens (or telomere dysfunction) induce genetic instability: associated‐selection model
Author(s) -
Blagosklonny Mikhail V
Publication year - 2001
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(01)02894-0
Subject(s) - carcinogen , telomerase , telomere , biology , mutation , dna repair , dna damage , limiting , genetics , selection (genetic algorithm) , genome instability , dna , cancer research , gene , computer science , mechanical engineering , engineering , artificial intelligence
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.