In response to genotoxic stress, cells activate a complex kinase-based signaling network, which is commonly referred to as the DNA damage response (DDR). Activation of this signaling cascade leads to cell cycle arrest, initiation of DNA repair, or, if the lesions are beyond repair capacity triggers additional pathways leading to cell death or senescence. Traditionally, the DDR has been subdivided into two major kinase branches, namely ATR and its downstream effector kinase Chk1, as well as ATM, which signals through its downstream kinase Chk2. Both of these kinase cascades ultimately converge on p53 and the Cdc25 cell cycle regulators. Upon phosphorylation at N-terminal residues, p53 becomes stabilized and translocates into the nucleus where it acts as a transcription factor to transactivate numerous target genes including Cdk inhibitors, such as CDKN1A or pro-apoptotic target genes, such as PUMA, BAX and BAK. However, recent work has demonstrated that the DDR network extends far beyond the ATR/Chk1 and ATM/Chk2 axes. For instance, it has been shown that there is extensive cross-talk between the DDR and the NFkB pathway, which mediates cell survival in response to various types of cellular stress. Furthermore, the DDR appears to be intimately involved in activating the innate immune system to damaged cells.
Intriguingly, components of the DDR network are among the most commonly mutated genes in human malignancies. It is thought that these DDR defects contribute to tumorigenesis by promoting a ‘mutator-phenotype’ allowing the acquisition of additional genetic lesions driving transformation. However, these extensively rewired DDR signaling pathways, which molecularly distinguish normal cells from cancer cells, also offer ample opportunity to specifically target tumor cells therapeutically. For instance, tumor cells carrying disabling mutations in BRCA1 or BRCA2 were recently shown to display hypersensitivity against pharmacological repression of the base excision repair mechanism through PARP1 inhibitors. Similarly, ATM-defective tumors and lymphomas display a robust non-oncogene addiction to DNA-PKcs. This Research Topic is aimed at comprehensive investigations of basic and novel mechanisms that underlie the eukaryotic DNA damage response in cancer and aging. Special emphasis will be placed on actionable molecular liabilities that are associated with the re-wiring of the DDR in human tumors.
In response to genotoxic stress, cells activate a complex kinase-based signaling network, which is commonly referred to as the DNA damage response (DDR). Activation of this signaling cascade leads to cell cycle arrest, initiation of DNA repair, or, if the lesions are beyond repair capacity triggers additional pathways leading to cell death or senescence. Traditionally, the DDR has been subdivided into two major kinase branches, namely ATR and its downstream effector kinase Chk1, as well as ATM, which signals through its downstream kinase Chk2. Both of these kinase cascades ultimately converge on p53 and the Cdc25 cell cycle regulators. Upon phosphorylation at N-terminal residues, p53 becomes stabilized and translocates into the nucleus where it acts as a transcription factor to transactivate numerous target genes including Cdk inhibitors, such as CDKN1A or pro-apoptotic target genes, such as PUMA, BAX and BAK. However, recent work has demonstrated that the DDR network extends far beyond the ATR/Chk1 and ATM/Chk2 axes. For instance, it has been shown that there is extensive cross-talk between the DDR and the NFkB pathway, which mediates cell survival in response to various types of cellular stress. Furthermore, the DDR appears to be intimately involved in activating the innate immune system to damaged cells.
Intriguingly, components of the DDR network are among the most commonly mutated genes in human malignancies. It is thought that these DDR defects contribute to tumorigenesis by promoting a ‘mutator-phenotype’ allowing the acquisition of additional genetic lesions driving transformation. However, these extensively rewired DDR signaling pathways, which molecularly distinguish normal cells from cancer cells, also offer ample opportunity to specifically target tumor cells therapeutically. For instance, tumor cells carrying disabling mutations in BRCA1 or BRCA2 were recently shown to display hypersensitivity against pharmacological repression of the base excision repair mechanism through PARP1 inhibitors. Similarly, ATM-defective tumors and lymphomas display a robust non-oncogene addiction to DNA-PKcs. This Research Topic is aimed at comprehensive investigations of basic and novel mechanisms that underlie the eukaryotic DNA damage response in cancer and aging. Special emphasis will be placed on actionable molecular liabilities that are associated with the re-wiring of the DDR in human tumors.
