Adaptation in replicative senescence: a risky business

Human polo-like kinase 1 (PLK1) is essential during mitosis and in the maintenance of genomic stability. PLK1 is overexpressed in human tumours and has prognostic potential in cancer, indicating its involvement in carcinogenesis and its potential as a therapeutic target. The use of different PLK1 inhibitors has increased our knowledge of mitotic regulation and allowed us to assess their ability to suppress tumour growth in vivo. We address the structural features of the kinase domain and the unique polo-box domain of PLK1 that are most suited for drug development and discuss our current understanding of the therapeutic potential of PLK1.

Yeast cells lacking a functional EST1 gene show progressive shortening of the terminal G1-3T telomeric repeats and a parallel increase in the frequency of cell death. Although the majority of the cells in an est1- culture die, a minor subpopulation survives the potentially lethal consequences of the est1 mutation. We show that these est1- survivors arise as a result of the amplification and acquisition of subtelomeric elements (and their deletion derivatives) by a large number of telomeres. Hence, even when the primary pathway for telomere replication is defective, an alternative backup pathway can restore telomere function and keep the cell alive.

Saccharomyces cells suffering a single unrepairable double-strand break (DSB) exhibit a long, but transient arrest at G2/M. hdf1 cells, lacking Ku70p, fail to escape from this RAD9/RAD17-dependent checkpoint. The effect of hdf1 results from its accelerated 5' to 3' degradation of the broken chromosome. Permanent arrest in hdf1 cells is suppressed by rad50 or mre11 deletions that retard this degradation. Wild-type HDF1 cells also become permanently arrested when they experience two unrepairable DSBs. Both DSB-induced arrest conditions are suppressed by a mutation in the single-strand binding protein, RPA. We suggest that escape from the DNA damage-induced G2/M checkpoint depends on the extent of ssDNA created at broken chromosome ends. RPA appears to play a key intermediate step in this adaptation.