Exploiting DNA repair pathways for tumor sensitization, mitigation of resistance, and normal tissue protection in radiotherapy

Nickoloff, Jac A.; Taylor, Lynn E.; Sharma, Neelam; Kato, Takamitsu A.

doi:10.20517/cdr.2020.89

Cited by 19 publications

(17 citation statements)

References 236 publications

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“…Replication stress causes genome instability that drives cancer progression, and it is caused by oncogenic stress and damage induced by genotoxic chemo-and radiotherapeutics. The DDR plays critical roles in managing replication stress, and inhibitors of DDR factors are promising targets to effect tumor-specific cell killing in mono-therapy or as adjuncts to genotoxic therapy (O'Connor, 2015;Pearl et al, 2015;Kirsch, 2018;Pilie et al, 2019;Trenner and Sartori, 2019;Nickoloff et al, 2020b). Several specific and broader questions remain.…”

Section: Discussionmentioning

confidence: 99%

“…Cells initially respond to replication stress by protecting stalled forks and maintaining replisomes until the stress is resolved, otherwise various mechanisms are employed to restart or rescue the fork to ensure timely completion of DNA replication before mitosis. The DDR is important because defects in DDR proteins typically cause genome instability that can drive carcinogenesis (Tubbs and Nussenzweig, 2017), and because DDR proteins are important targets to augment cancer therapy (Nickoloff et al, 2017;Desai et al, 2018;Pilie et al, 2019;Nickoloff et al, 2020b;Baillie and Stirling, 2021). Central to the DDR are three members of the phosphatidyl inositol 3′ kinase-related kinase (PIKK) family, DNA-PKcs, ATM, and ATR, all of which play important roles in DSB repair.…”

Section: Dna Damage and Replication Stress Responsesmentioning

confidence: 99%

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The Safe Path at the Fork: Ensuring Replication-Associated DNA Double-Strand Breaks are Repaired by Homologous Recombination

et al. 2021

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Cells must replicate and segregate their DNA to daughter cells accurately to maintain genome stability and prevent cancer. DNA replication is usually fast and accurate, with intrinsic (proofreading) and extrinsic (mismatch repair) error-correction systems. However, replication forks slow or stop when they encounter DNA lesions, natural pause sites, and difficult-to-replicate sequences, or when cells are treated with DNA polymerase inhibitors or hydroxyurea, which depletes nucleotide pools. These challenges are termed replication stress, to which cells respond by activating DNA damage response signaling pathways that delay cell cycle progression, stimulate repair and replication fork restart, or induce apoptosis. Stressed forks are managed by rescue from adjacent forks, repriming, translesion synthesis, template switching, and fork reversal which produces a single-ended double-strand break (seDSB). Stressed forks also collapse to seDSBs when they encounter single-strand nicks or are cleaved by structure-specific nucleases. Reversed and cleaved forks can be restarted by homologous recombination (HR), but seDSBs pose risks of mis-rejoining by non-homologous end-joining (NHEJ) to other DSBs, causing genome rearrangements. HR requires resection of broken ends to create 3’ single-stranded DNA for RAD51 recombinase loading, and resected ends are refractory to repair by NHEJ. This Mini Review highlights mechanisms that help maintain genome stability by promoting resection of seDSBs and accurate fork restart by HR.

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Section: Discussionmentioning

confidence: 99%

Section: Dna Damage and Replication Stress Responsesmentioning

confidence: 99%

The Safe Path at the Fork: Ensuring Replication-Associated DNA Double-Strand Breaks are Repaired by Homologous Recombination

et al. 2021

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“…The DDR is critical for maintaining genome stability and preventing cancer. The often-altered DDR in cancer cells can thwart the action of antitumor chemo-and radiotherapeutics, thus DDR factors are important therapeutic targets (12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Metnase and EEPD1: DNA Repair Functions and Potential Targets in Cancer Therapy

et al. 2022

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Cells respond to DNA damage by activating signaling and DNA repair systems, described as the DNA damage response (DDR). Clarifying DDR pathways and their dysregulation in cancer are important for understanding cancer etiology, how cancer cells exploit the DDR to survive endogenous and treatment-related stress, and to identify DDR targets as therapeutic targets. Cancer is often treated with genotoxic chemicals and/or ionizing radiation. These agents are cytotoxic because they induce DNA double-strand breaks (DSBs) directly, or indirectly by inducing replication stress which causes replication fork collapse to DSBs. EEPD1 and Metnase are structure-specific nucleases, and Metnase is also a protein methyl transferase that methylates histone H3 and itself. EEPD1 and Metnase promote repair of frank, two-ended DSBs, and both promote the timely and accurate restart of replication forks that have collapsed to single-ended DSBs. In addition to its roles in HR, Metnase also promotes DSB repair by classical non-homologous recombination, and chromosome decatenation mediated by TopoIIα. Although mutations in Metnase and EEPD1 are not common in cancer, both proteins are frequently overexpressed, which may help tumor cells manage oncogenic stress or confer resistance to therapeutics. Here we focus on Metnase and EEPD1 DNA repair pathways, and discuss opportunities for targeting these pathways to enhance cancer therapy.

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“…In the first article, Nickoloff et al [ 10 ] discuss exploiting the DNA repair pathways to improve radiosensitivity of the tumor and to prevent resistance while also protecting healthy tissue during radiotherapy. Currently, more than half of the cancer patients are treated with radiotherapy, which induces among others cytotoxic DNA lesions.…”

mentioning

confidence: 99%

“…Moreover, by targeting signaling and repair of DNA lesions, we aim to prevent compensatory activation of DNA repair pathways as a resistance mechanism. As such, the concept of targeting DNA repair has been successfully developed in the last decade to a bona fide therapeutic strategy with poly (ADP-ribose) polymerase inhibitors (PARPi) to treat DNA repair deficient breast, ovarian, pancreatic, and prostate cancers [3][4][5][6][7][8][9] . These successes have stimulated the clinical development of small molecules that target other key components of the DNA damage response and repair pathways.…”

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confidence: 99%