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Chemotherapy induced DNA damage response: convergence of drugs and pathways.

Woods D, Turchi JJ - Cancer Biol. Ther. (2013)

Bottom Line: Chemotherapeutics target rapidly dividing cancer cells by directly or indirectly inducing DNA damage.However, the activation of these various pathways has similar results including DNA repair, suppression of global general translation, cell cycle arrest and, ultimately, either cell survival or cell death.This review will focus on a series of chemotherapy-induced DNA lesions and highlight recent advances in our understanding of the DDR, the DNA repair pathways it activates and the cellular consequences of these converging pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.

ABSTRACT
Chemotherapeutics target rapidly dividing cancer cells by directly or indirectly inducing DNA damage. Upon recognizing DNA damage, cells initiate a variety of signaling pathways collectively referred to as the DNA damage response (DDR). Interestingly, the pathways used to elicit this response are as varied as the types of DNA damage induced. However, the activation of these various pathways has similar results including DNA repair, suppression of global general translation, cell cycle arrest and, ultimately, either cell survival or cell death. This review will focus on a series of chemotherapy-induced DNA lesions and highlight recent advances in our understanding of the DDR, the DNA repair pathways it activates and the cellular consequences of these converging pathways.

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Related in: MedlinePlus

Figure 2. Summary of intra- and inter- PIKK regulation. DNA-PKcs and ATM undergo autophosphorylation. DNA-PKcs is a phosphorylation target of ATM and ATR while DNA-PKcs promotes ATM transcription.
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Figure 2: Figure 2. Summary of intra- and inter- PIKK regulation. DNA-PKcs and ATM undergo autophosphorylation. DNA-PKcs is a phosphorylation target of ATM and ATR while DNA-PKcs promotes ATM transcription.

Mentions: A theme in the initiation of DDR by the PIKK is the interdependence of the kinases in regulation. Among the 40 sites of DNA-PKcs that become phosphorylated only a few have been shown to significantly alter repair. Of these sites the ABCDE cluster mentioned above is perhaps the most significant and is phosphorylated by ATM following DSBs and ATR following UV irradiation.24,25 DNA-PKcs, on the other hand, seems to be involved in a feedback loop regulating the expression of ATM as evidenced by the fact that cells with knocked down DNA-PKcs have reduced levels of ATM. Further, it was shown that when cell lines that were DNA-PKcs were transfected with DNA-PKcs plasmids, ATM levels rose.26 The control of both of these events was shown to be at the transcriptional level suggesting that DNA-PKcs regulates the transcription of ATM. Additionally, the autophosphorylation of DNA-PKcs at the JK and N sites promotes HR, which activates ATR and ATM.23 Recently, MRN and CtIP, whose resection activity has been shown to promote HR and stimulate ATM activity, were shown to promote NHEJ following etoposide treatment of cells in G1.27 This is seemingly in contrast to work in yeast which suggests that Mre11 and CtIP are responsible for the release of Ku from dsDNA termini and promoting HR.28 Whether this functional relationship is also retained in mammals remains untested. Because Ku activates and regulates DNA-PKcs activity, it is important that the influence of Mre11 and CtIP on displacing Ku from DNA be investigated further. This model however, is consistent with data demonstrating that ATM phosphorylation of TOPbp1 in conjunction with NBS1 stimulated ATR activity. These and other data provide convincing evidence that the PIKKSs regulate each other directly through phosphorylation and transcription while indirectly regulating each other by promoting the pathways which in turn activate other PIKKs (Fig. 2).


Chemotherapy induced DNA damage response: convergence of drugs and pathways.

Woods D, Turchi JJ - Cancer Biol. Ther. (2013)

Figure 2. Summary of intra- and inter- PIKK regulation. DNA-PKcs and ATM undergo autophosphorylation. DNA-PKcs is a phosphorylation target of ATM and ATR while DNA-PKcs promotes ATM transcription.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672181&req=5

Figure 2: Figure 2. Summary of intra- and inter- PIKK regulation. DNA-PKcs and ATM undergo autophosphorylation. DNA-PKcs is a phosphorylation target of ATM and ATR while DNA-PKcs promotes ATM transcription.
Mentions: A theme in the initiation of DDR by the PIKK is the interdependence of the kinases in regulation. Among the 40 sites of DNA-PKcs that become phosphorylated only a few have been shown to significantly alter repair. Of these sites the ABCDE cluster mentioned above is perhaps the most significant and is phosphorylated by ATM following DSBs and ATR following UV irradiation.24,25 DNA-PKcs, on the other hand, seems to be involved in a feedback loop regulating the expression of ATM as evidenced by the fact that cells with knocked down DNA-PKcs have reduced levels of ATM. Further, it was shown that when cell lines that were DNA-PKcs were transfected with DNA-PKcs plasmids, ATM levels rose.26 The control of both of these events was shown to be at the transcriptional level suggesting that DNA-PKcs regulates the transcription of ATM. Additionally, the autophosphorylation of DNA-PKcs at the JK and N sites promotes HR, which activates ATR and ATM.23 Recently, MRN and CtIP, whose resection activity has been shown to promote HR and stimulate ATM activity, were shown to promote NHEJ following etoposide treatment of cells in G1.27 This is seemingly in contrast to work in yeast which suggests that Mre11 and CtIP are responsible for the release of Ku from dsDNA termini and promoting HR.28 Whether this functional relationship is also retained in mammals remains untested. Because Ku activates and regulates DNA-PKcs activity, it is important that the influence of Mre11 and CtIP on displacing Ku from DNA be investigated further. This model however, is consistent with data demonstrating that ATM phosphorylation of TOPbp1 in conjunction with NBS1 stimulated ATR activity. These and other data provide convincing evidence that the PIKKSs regulate each other directly through phosphorylation and transcription while indirectly regulating each other by promoting the pathways which in turn activate other PIKKs (Fig. 2).

Bottom Line: Chemotherapeutics target rapidly dividing cancer cells by directly or indirectly inducing DNA damage.However, the activation of these various pathways has similar results including DNA repair, suppression of global general translation, cell cycle arrest and, ultimately, either cell survival or cell death.This review will focus on a series of chemotherapy-induced DNA lesions and highlight recent advances in our understanding of the DDR, the DNA repair pathways it activates and the cellular consequences of these converging pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.

ABSTRACT
Chemotherapeutics target rapidly dividing cancer cells by directly or indirectly inducing DNA damage. Upon recognizing DNA damage, cells initiate a variety of signaling pathways collectively referred to as the DNA damage response (DDR). Interestingly, the pathways used to elicit this response are as varied as the types of DNA damage induced. However, the activation of these various pathways has similar results including DNA repair, suppression of global general translation, cell cycle arrest and, ultimately, either cell survival or cell death. This review will focus on a series of chemotherapy-induced DNA lesions and highlight recent advances in our understanding of the DDR, the DNA repair pathways it activates and the cellular consequences of these converging pathways.

Show MeSH
Related in: MedlinePlus