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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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Figure 1. Summary of PIKK Activation pathways. Preferential DNA substrates and recognition complexes are presented. (A) ATM responds to long 3′ single stranded regions via the MRN complex. (B) ATR is activated by short 3′ regions near duplex junctions via RPA:ATRIP and TopBP1. Protein complexes that tether the PIKKs to DNA are colored green while proteins involved in activating the PIKKs are indicated by the squares. (C) DNA-PKcs recognizes double stranded DNA termini via Ku.
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Figure 1: Figure 1. Summary of PIKK Activation pathways. Preferential DNA substrates and recognition complexes are presented. (A) ATM responds to long 3′ single stranded regions via the MRN complex. (B) ATR is activated by short 3′ regions near duplex junctions via RPA:ATRIP and TopBP1. Protein complexes that tether the PIKKs to DNA are colored green while proteins involved in activating the PIKKs are indicated by the squares. (C) DNA-PKcs recognizes double stranded DNA termini via Ku.

Mentions: Ataxia-telangiectasia mutated (ATM) is a 315kDa protein that plays a major role in initiating the DDR. ATM remains a homodimer while inactive, but upon activation undergoes trans-autophosphorylation at serine 1981, leading to disruption of the dimer and allowing monomeric ATM to be recruited to dsDNA via an interaction with the MRN complex.4 While this phosphorylation event may be necessary for disruption of the dimmer, data suggest that it is not sufficient (See next paragraph). How this initial autophosphorylation event is stimulated is not well understood but may rely on chromatin relaxation.4 The nuclease activity of the MRN complex results in 3′ssDNA which along with its interaction with the C-terminus of Nbs1 stimulates ATM kinase activity and ultimately promotes homologous recombination (HR) (Fig. 1A).5 In an independent activation pathway, ATM has been shown to be activated by ATMIN under hypotonic stress which is independent of Nbs1 interactions.6 Interestingly, HR is restricted to S and G2 phases of the cell cycle, yet ATM is activated following DSBs regardless of cell cycle stage.7 Some data suggests that DNA resection is a major component of whether ATM activation promotes HR or NHEJ. ATM activation following damage occurring in G1 leads to a minute amount of DNA resection due to low levels of cyclin dependent kinases and promotes NHEJ. ATM activation in S or G2, when cyclin dependent kinase levels are high, promotes DNA resection by MRN leading to HR promotion via ATR signaling chapman.5 Regardless S checkpoint cell cycle arrest is a hallmark of ATM activation.8 Upon recruitment of ATM to DSBs via the MRN complex, monomeric ATM undergoes autophosphorylation at additional sites including the recently identified Serine 367 and Serine 2996.9 Importantly, when these sites were mutated to phosphor-ablating alanines ATM was unable to arrest the cell cycle at the S checkpoint, suggesting these phosphorylation events are essential in the DDR.9


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

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

Figure 1. Summary of PIKK Activation pathways. Preferential DNA substrates and recognition complexes are presented. (A) ATM responds to long 3′ single stranded regions via the MRN complex. (B) ATR is activated by short 3′ regions near duplex junctions via RPA:ATRIP and TopBP1. Protein complexes that tether the PIKKs to DNA are colored green while proteins involved in activating the PIKKs are indicated by the squares. (C) DNA-PKcs recognizes double stranded DNA termini via Ku.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Figure 1. Summary of PIKK Activation pathways. Preferential DNA substrates and recognition complexes are presented. (A) ATM responds to long 3′ single stranded regions via the MRN complex. (B) ATR is activated by short 3′ regions near duplex junctions via RPA:ATRIP and TopBP1. Protein complexes that tether the PIKKs to DNA are colored green while proteins involved in activating the PIKKs are indicated by the squares. (C) DNA-PKcs recognizes double stranded DNA termini via Ku.
Mentions: Ataxia-telangiectasia mutated (ATM) is a 315kDa protein that plays a major role in initiating the DDR. ATM remains a homodimer while inactive, but upon activation undergoes trans-autophosphorylation at serine 1981, leading to disruption of the dimer and allowing monomeric ATM to be recruited to dsDNA via an interaction with the MRN complex.4 While this phosphorylation event may be necessary for disruption of the dimmer, data suggest that it is not sufficient (See next paragraph). How this initial autophosphorylation event is stimulated is not well understood but may rely on chromatin relaxation.4 The nuclease activity of the MRN complex results in 3′ssDNA which along with its interaction with the C-terminus of Nbs1 stimulates ATM kinase activity and ultimately promotes homologous recombination (HR) (Fig. 1A).5 In an independent activation pathway, ATM has been shown to be activated by ATMIN under hypotonic stress which is independent of Nbs1 interactions.6 Interestingly, HR is restricted to S and G2 phases of the cell cycle, yet ATM is activated following DSBs regardless of cell cycle stage.7 Some data suggests that DNA resection is a major component of whether ATM activation promotes HR or NHEJ. ATM activation following damage occurring in G1 leads to a minute amount of DNA resection due to low levels of cyclin dependent kinases and promotes NHEJ. ATM activation in S or G2, when cyclin dependent kinase levels are high, promotes DNA resection by MRN leading to HR promotion via ATR signaling chapman.5 Regardless S checkpoint cell cycle arrest is a hallmark of ATM activation.8 Upon recruitment of ATM to DSBs via the MRN complex, monomeric ATM undergoes autophosphorylation at additional sites including the recently identified Serine 367 and Serine 2996.9 Importantly, when these sites were mutated to phosphor-ablating alanines ATM was unable to arrest the cell cycle at the S checkpoint, suggesting these phosphorylation events are essential in the DDR.9

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