The most frequent genetic alterations in melanoma are gain-of-function (GOF) mutations in BRAF, which result in RAF-MEK-ERK signaling pathway addiction. Despite therapeutic success of RAF and MEK inhibitors in treating BRAF-mutant tumors, a major challenge is the inevitable emergence of drug resistance, which often involves reactivation of the MAPK pathway. Interestingly, resistant tumors are often sensitive to drug withdrawal, suggesting that hyperactivation of the MAPK pathway is not tolerated.
View Article and Find Full Text PDFDNA Repair (Amst)
January 2016
Cells are constantly exposed to assaults that cause DNA damage, which must be detected and repaired to prevent genome instability. The DNA damage response is mediated by key kinases that activate various signaling pathways. In Saccharomyces cerevisiae, one of these kinases is Mec1, which phosphorylates numerous targets, including H2A and the DNA damage protein Rtt107.
View Article and Find Full Text PDFThe DNA damage response (DDR) is a dynamic process that is crucial for protecting the cell from challenges to genome integrity. Although many genome-wide studies in Saccharomyces cerevisiae have identified genes that contribute to resistance to DNA-damaging agents, more work is needed to elucidate the changes in genetic interaction networks in response to DNA lesions. Here we used conditional epistatic miniarray profiling to analyze the genetic interaction networks of the DDR genes RTT107, SLX4, and HRQ1 under three DNA-damaging conditions: camptothecin, hydroxyurea, and methyl methanesulfonate.
View Article and Find Full Text PDFGenome integrity is maintained by a network of DNA damage response pathways, including checkpoints and DNA repair processes. In Saccharomyces cerevisiae, the BRCT domain-containing protein Rtt107/Esc4 is required for the restart of DNA replication after successful repair of DNA damage and for cellular resistance to DNA-damaging agents. In addition to its well characterized interaction with the endonuclease Slx4, Rtt107 interacts with a number of other DNA repair and recombination proteins.
View Article and Find Full Text PDFGenomic integrity is maintained by the coordinated interaction of many DNA damage response pathways, including checkpoints, DNA repair processes, and cell cycle restart. In Saccharomyces cerevisiae, the BRCA1 C-terminal domain-containing protein Rtt107/Esc4 is required for restart of DNA replication after successful repair of DNA damage and for cellular resistance to DNA-damaging agents. Rtt107 and its interaction partner Slx4 are phosphorylated during the initial phase of DNA damage response by the checkpoint kinases Mec1 and Tel1.
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