The RAD9 Gene Controls the Cell Cycle Response to DNA Damage in Saccharomyces cerevisiae

  • Weinert T
  • Hartwell L
  • Hartwell H
 et al. 
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Cell division is arrested in many organisms in response to DNA damage. Examinations of the genetic basis for this response in the yeast Saccharomyces cerevisiae indicate that the RAD9 gene product is essential for arrest of cell division induced by DNA damage. Wild-type haploid cells irradiated with x-rays either arrest or delay cell division in the G2 phase of the cell cyde. Irradiated Gl and M phase haploid cells arrest irreversibly in G2 and die, whereas irradiated G2 phase haploid cells delay in G2 for a time proportional to the extent of damage before resuming cell division. In contrast, irradiated rad9 cells in any phase ofthe cycle do not delay cell division in G2, but continue to divide for several generations and die. How-ever, efficient DNA repair can occur in irradiated rad9 cells if irradiated cells are blocked for several hours in G2 by treatment with a microtubule poison. The RAD9-dependent response detects potentially lethal DNA dam-age and causes arrest of cells in G2 until such damage is repaired. C ELL DIVISION IS CONTROLLED IN RESPONSE TO VARIOUS physiological changes, including damage to DNA. Bacteria and animal cells respond to DNA damage by delaying cell division. In bacteria, the purpose of division delay has not been clearly demonstrated although the genetic and molecular basis ofthe response is well understood; DNA damage activates the RecA protease leading to synthesis of an inhibitor of cell septation (1). In eukaryotes the nature and purpose of DNA damage-sensitive divi-sion delay is understood although underlying mechanisms remain obscure. DNA damage induces arrest in the G2 phase of the cell cycle, after DNA replication and before mitosis (2-9). The following observations suggest that G2 arrest may simply provide ample time for the cell to repair DNA lesions and thus ensure integrity of condensed chromosomes for segregation at mitosis. The role of G2 arrest in response to DNA damage has been demonstrated in mammalian cells through the use of agents that cause the cells to fail to arrest. Chromosomes either in S phase (undergoing replication) or in G2 (completely replicated but not condensed) could be induced to condense either by fusion with a mitotic cell or by treatment with caffeine (4-6). Breaks were revealed in the condensed chromosomes from cells that had been forced prematurely from the G2 arrest induced by DNA damage, whereas fewer breaks were observed in chromosomes either forced to condense after a G2 delay or permitted to progress naturally to mitosis (4, 5). Furthermore, cell viability was lower if DNA damaged cells were forced from G2 arrest by treatment with caffeine than when cells were permitted to delay in G2 (6). These results demonstrate that DNA damage repair occurs during G2 delay, that cell division in the presence of chromosome damage is lethal, and hence that G2 division delay is essential for viability in cells with damaged DNA. Furthermore, since treatment with caffeine or mitotic cell fusion bypasses G2 arrest, this arrest is likely to be mediated by a control mechanism rather than by structural con-straints of the damaged DNA that directly prevent entry into

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  • Ted A Weinert

  • Leland H Hartwell

  • H Hartwell

  • T E D A Weinert

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