1. Targeting the DNA Damage Response in Cancer
Mark J. O’Connor 
Molecular Cell 
Volume 60, Issue 4, Pages (November 2015)
DOI: /j.molcel
Copyright © 2015 Elsevier Inc. Terms and Conditions

2. Figure 1 DDR Pathway and Cell-Cycle Targets
(A) DDR pathway targets, including the rationale for targeting these pathways. Shown in bold are SSB and DSB repair targets that are currently being evaluated in clinical trials. ∗MTH1/dNTP sanitation proposed as an opportunity, but emerging data have not been able to provide validation (Alwan et al., 2015).
(B) DDR cell-cycle targets. DDR targets are shown for each cell-cycle checkpoint, with those in bold currently being evaluated in clinical trials. APE1, AP endonuclease 1; ATM, ataxia-telangiectasia mutated; ATR, ataxia-telangiectasia and Rad3-related; DNA-PK, DNA-dependent protein kinase; PARP, poly(ADP-ribose) polymerase; RTx, radiotherapy; Topo, topoisomerase.
Molecular Cell  , DOI: ( /j.molcel )
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3. Figure 2
Key Differences in Cancer DDR that Provide a Rationale for Drug Targeting
Loss of one or more DDR pathways, increased replication stress and higher levels of endogenous DNA damage are all differentiating aspects of cancer DDR that can be targeted therapeutically.
Left image, ©Suravid. Dreamstime.com - Golden Gene In DNA Photo; middle image, ©paulista/Shutterstock.com.
Molecular Cell  , DOI: ( /j.molcel )
Copyright © 2015 Elsevier Inc. Terms and Conditions

4. Figure 3
Loss of DDR Pathways during Tumorigenesis Results in DDR Dependencies that Can Be Targeted in the Resulting Cancer
With a full complement of repair pathways, normal cells can compensate for the loss of individual DDR pathways. However, loss of one or more DDR pathway(s) in response to oncogenic stress can leave cancer cells vulnerable to inhibition of remaining pathways and induce cancer-specific cell death through the process of synthetic lethality.
Molecular Cell  , DOI: ( /j.molcel )
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5. Figure 4 Olaparib Synthetic Lethality in BRCAm Tumors
Poly(ADP-ribose) polymerases (PARPs) repair DNA SSBs through the BER pathway. PARP inhibitors, such as olaparib, prevent repair by trapping the inactivated PARP onto the SSB, resulting in the generation of DNA DSBs during the replication process. In tumors with a homologous recombination deficiency (HRD), such as a BRCA1/2 mutation, the low-fidelity repair mechanism of NHEJ leads to increasing genetic instability and ultimately death of the tumor cell.
Molecular Cell  , DOI: ( /j.molcel )
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6. Figure 5 Activation of DDR in Response to Replication Stress
Replication fork (RF) stress can cause the polymerase (Pol) to stall leading to extended stretches of ssDNA that are coated by replication protein A (RPA). ATR-interacting protein (ATRIP) binds to the RPA-coated ssDNA, recruiting ATR to the site of DNA damage. Once the ATR-ATRIP complex interacts with TopBP1, ATR signaling can be activated with CHK1 as a key substrate. The replication stress response when activated helps to prevent replication fork collapse and the generation of cytotoxic DNA DSBs.
Molecular Cell  , DOI: ( /j.molcel )
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7. Figure 6 Strategy for the Use of DDR Inhibitors as Anticancer Agents
The strategy for the development of DDR-targeted agents is to cause the maximum amount of DNA damage during the G1 and S phases of the cell cycle, and then prevent DNA repair during G2. This strategy maximizes the amount of DNA damage that is taken into mitosis.
Molecular Cell  , DOI: ( /j.molcel )
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