Abstract
Author SummaryCellular surveillance mechanisms, termed checkpoints, have evolved to recognize the presence of DNA damage, halt cell division, and promote repair. The purpose of these checkpoints is to prevent the next generation of cells from inheriting a damaged genome. However, after futile attempts at repair over several hours of growth arrest, yeast cells eventually adapt and continue with cell division despite the presence of persistent DNA lesions. This process of adaptation employs CDC5, a kinase that also has essential roles in promoting cell division in the absence of DNA damage. We found that increasing levels of Cdc5 promote adaptation by suppressing the hyperphosphorylation of the checkpoint kinase Rad53, which in turn suppresses the DNA damage checkpoint and relieves cell division arrest. Intriguingly, overexpression of PLK1, the human homolog of CDC5, has been reported in various tumor types and has been linked to poor prognosis. Therefore, understanding the mechanism of adaptation in yeast may provide valuable insight into the role of PLK1 overexpression in tumor progression. Two related papers, published in PLoS Biology (van Vugt et al., doi:10.1371/journal.pbio.1000287) and PLoS Genetics (Donnianni et al., doi:10.1371/journal.pgen.1000763), similarly investigate the phenomenon of checkpoint adaptation.
Highlights
Both exogenous pressures and normal cellular processes place stresses on the genome that commonly results in DNA lesions, such as DNA adducts, nicks, and breaks
The 9-1-1 clamp is likely loaded onto DNA at single-stranded DNA (ssDNA)-dsDNA junctions that are created by resection, in a manner similar to the proposed mechanism of PCNA loading at sites of replication [10,11,12,13]
We found that increasing levels of Cdc5 promote adaptation by suppressing the hyperphosphorylation of the checkpoint kinase Rad53, which in turn suppresses the DNA damage checkpoint and relieves cell division arrest
Summary
Both exogenous pressures and normal cellular processes place stresses on the genome that commonly results in DNA lesions, such as DNA adducts, nicks, and breaks. A robust checkpoint response has evolved to quickly react to the presence of damaged DNA. When triggered, this evolutionarily conserved checkpoint arrests the cell cycle and promotes repair to maintain the integrity of the genome for the generation of cells. The Saccharomyces cerevisiae checkpoint sensor complexes, which include the checkpoint clamp and the Mec kinase, recognize the exposed ssDNA and accumulate at the break site [6,7,8,9]. Tel accumulates at DSBs and contributes to initial checkpoint activation [9], functioning in parallel with the major yeast sensor kinase Mec, in contrast to the major role of the mammalian Tel homologue, ATM [14,15]. The homologous mammalian kinase, ATR, and its interacting partner, ATRIP, localize to DNA damage via RPA [8]
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