The FASEB Journal, Vol 7, 1188-1191, Copyright © 1993 by The Federation of American Societies for Experimental Biology

REVIEWS

Cell cycle control, DNA repair and initiation of carcinogenesis

WK Kaufmann and DG Kaufman
Department of Pathology, University of North Carolina at Chapel Hill 27599.

We hypothesize that degradation of controls that normally act to inhibit cell proliferation is an early step in carcinogenesis. This alteration gives rise to initiated clones that display a selective growth advantage over normal cells when subjected to appropriate growth- promoting influences. In cell culture, such initiated cells also may display a selective growth advantage that lets them proliferate under conditions in which normal cell growth ceases. Cells with these properties have been designated enhanced-growth variants (EGVs)2 (1) or extended life span variants (ELVs) (2). We propose that the EGV/ELV phenotypes in vitro and initiation of carcinogenesis in vivo are consequences of genetic changes in pathways that regulate the passage of cells through the cell cycle. These regulatory pathways normally delay or arrest cell cycle progression in response to homeostatic regulators and DNA damage. DNA damage induced by a variety of genotoxic agents triggers delays in cycle progression at three steps of the cell cycle. Two of these involve delays in progression from G1 into S phase and G2 into mitosis. The third occurs within S phase cells and involves reduction in the rate of initiation of DNA synthesis in replicon clusters. If these cycle delay responses fail, damaged DNA may be replicated before it is adequately repaired. This would enhance production of additional genetic alterations. Thus, mutations in genes that normally exert a negative control over cell cycle progression may give cells a growth advantage and make the cells more genetically unstable.

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