Chemotherapy induced DNA damage response: convergence of drugs and pathways

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.

Keywords: ATM; ATR; DNA damage; DNA-PK; PIKK; chemotherapy; cisplatin; signaling.

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.

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.

Figure 3. Chemical structures of DNA damaging chemotherapeutics.

Figure 4. Chemical structures of natural product-based DNA damaging therapeutics.