Abstract
The repair of DNA double-strand breaks (DSBs) is a critical cellular mechanism that exists to ensure genomic stability. DNA DSBs are the most deleterious type of insult to a cell’s genetic material and can lead to genomic instability, apoptosis, or senescence. Incorrectly repaired DNA DSBs have the potential to produce chromosomal translocations and genomic instability, potentially leading to cancer. The prevalence of DNA DSBs in cancer due to unregulated growth and errors in repair opens up a potential therapeutic window in the treatment of cancers. The cellular response to DNA DSBs is comprised of two pathways to ensure DNA breaks are repaired: homologous recombination and non-homologous end joining. Identifying chemotherapeutic compounds targeting proteins involved in these DNA repair pathways has shown promise as a cancer therapy for patients, either as a monotherapy or in combination with genotoxic drugs. From the beginning, there have been a number of chemotherapeutic compounds that have yielded successful responses in the clinic, a number that have failed (CGK-733 and iniparib), and a number of promising targets for future studies identified. This review looks in detail at how the cell responds to these DNA DSBs and investigates the chemotherapeutic avenues that have been and are currently being explored to target this repair process.
Highlights
Genomic stability at a cellular level requires precise, tightly coordinated pathways to detect DNA damage and either repair the damage or, if the damage is too great, ensure the cell dies via apoptosis or enters senescence
The prevalence of DNA double-strand breaks (DSBs) in cancer due to unregulated growth and errors in repair opens up a potential therapeutic window in the treatment of cancers.The cellular response to DNA DSBs is comprised of two pathways to ensure DNA breaks are repaired: homologous recombination and non-homologous end joining
This review looks in detail at how the cell responds to these DNA DSBs and investigates the chemotherapeutic avenues that have been and are currently being explored to target this repair process
Summary
Genomic stability at a cellular level requires precise, tightly coordinated pathways to detect DNA damage and either repair the damage or, if the damage is too great, ensure the cell dies via apoptosis or enters senescence. PF-00477736 is a potent, selective ATP-competitive small molecule inhibitor of Chk and was shown to abrogate cell cycle arrest induced by DNA damage and enhanced the cytotoxicity of clinically important chemotherapeutic agents, including gemcitabine and carboplatin both in vitro and in vivo in mouse xenografts [77]. The initiation of the DDR by RPA is mediated by protein– protein interactions involving the N-terminal domain of the p70 subunit with partner proteins, including the MRN complex [108], Rad51 [109], and BRCA2 [110] Inhibition of these interactions increases sensitivity toward DNA damage and replication stress and may be a potential strategy for cancer drug discovery. Due to the resection of DNA overhangs surrounding the DSB, NHEJ is sometimes considered the error-prone pathway of DNA
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