Yeast DNA damage response pathways and human disease

Abstract

All living organisms are constantly subjected to a diverse range of environmental genotoxins such as ultraviolet radiation, but even in a perfect environment, DNA damage would be unavoidable; DNA polymerases inevitably make errors, spontaneously stalled replication forks are at high risk to collapse into DNA double strand breaks and free radicals generated during normal cellular metabolism damage thousands of bases per cell per day. DNA damage that is not appropriately repaired leads to accumulating genome instability, which we now know is a major underlying cause of cancer development in humans. Conversely, most contemporary cancer therapies act by causing DNA damage. Interestingly, DNA damage response pathways are highly conserved throughout eukaryotic evolution, and this allows us to use budding yeast as a model to study the principles important for carcinogenesis and cancer therapies in human patients. In yeast and humans, conserved checkpoint proteins including FHA domain-containing kinases Rad53 and Chk2 play crucial roles in delaying the cell cycle in response to DNA damage, to allow for extra time for DNA repair. In addition, these kinases also interact with mRNA poly(A)-tail nucleases to control gene expression after DNA damage at the post-transcriptional level, and via their FHA domains they bind conserved DNA repair proteins. Surprisingly, Rad53 via its conserved FHA domain also appears to be involved in regulating filamentous differentiation in pathogenic fungi, indicating that the analyses of yeast checkpoint responses may be of direct benefit for public health.