scholarly journals Recent advancements in PARP inhibitors-based targeted cancer therapy

2020 ◽  
Vol 3 (3) ◽  
pp. 187-201
Author(s):  
Ping Zhou ◽  
Justin Wang ◽  
Daniel Mishail ◽  
Cun-Yu Wang
Keyword(s):  
Molecular Mechanisms ◽  
Synthetic Lethality ◽  
Parp Inhibitors ◽  
Targeted Cancer Therapy ◽  
End Joining ◽  
Crucial Issue ◽  
New Class ◽  
Fda Approval ◽  
Non Homologous End Joining ◽  
Shed Light

Abstract Poly(ADP-ribose) polymerase inhibitors (PARPi) are a new class of agents with unparalleled clinical achievement for driving synthetic lethality in BRCA-deficient cancers. Recent FDA approval of PARPi has motivated clinical trials centered around the optimization of PARPi-associated therapies in a variety of BRCA-deficient cancers. This review highlights recent advancements in understanding the molecular mechanisms of PARP ‘trapping’ and synthetic lethality. Particular attention is placed on the potential extension of PARPi therapies from BRCA-deficient patients to populations with other homologous recombination-deficient backgrounds, and common characteristics of PARPi and non-homologous end-joining have been elucidated. The synergistic antitumor effect of combining PARPi with various immune checkpoint blockades has been explored to evaluate the potential of combination therapy in attaining greater therapeutic outcome. This has shed light onto the differing classifications of PARPi as well as the factors that result in altered PARPi activity. Lastly, acquired chemoresistance is a crucial issue for clinical application of PARPi. The molecular mechanisms underlying PARPi resistance and potential overcoming strategies are discussed.

scholarly journals Alternative Non-Homologous End-Joining: Error-Prone DNA Repair as Cancer’s Achilles’ Heel

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1392
Author(s):  
Daniele Caracciolo ◽  
Caterina Riillo ◽  
Maria Teresa Di Martino ◽  
Pierosandro Tagliaferri ◽  
Pierfrancesco Tassone
Keyword(s):  
Dna Repair ◽  
Genomic Instability ◽  
Molecular Mechanisms ◽  
Synthetic Lethality ◽  
Checkpoint Inhibitors ◽  
Precision Oncology ◽  
End Joining ◽  
Cancer Hallmarks ◽  
Promising Target ◽  
Non Homologous End Joining

Error-prone DNA repair pathways promote genomic instability which leads to the onset of cancer hallmarks by progressive genetic aberrations in tumor cells. The molecular mechanisms which foster this process remain mostly undefined, and breakthrough advancements are eagerly awaited. In this context, the alternative non-homologous end joining (Alt-NHEJ) pathway is considered a leading actor. Indeed, there is experimental evidence that up-regulation of major Alt-NHEJ components, such as LIG3, PolQ, and PARP1, occurs in different tumors, where they are often associated with disease progression and drug resistance. Moreover, the Alt-NHEJ addiction of cancer cells provides a promising target to be exploited by synthetic lethality approaches for the use of DNA damage response (DDR) inhibitors and even as a sensitizer to checkpoint-inhibitors immunotherapy by increasing the mutational load. In this review, we discuss recent findings highlighting the role of Alt-NHEJ as a promoter of genomic instability and, therefore, as new cancer’s Achilles’ heel to be therapeutically exploited in precision oncology.

Repairing DNA double-strand breaks by the prokaryotic non-homologous end-joining pathway

2009 ◽  
Vol 37 (3) ◽  
pp. 539-545 ◽  
Author(s):  
Nigel C. Brissett ◽  
Aidan J. Doherty
Keyword(s):  
Molecular Mechanisms ◽  
Model System ◽  
Double Strand Breaks ◽  
Repair Pathway ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Dsb Repair ◽  
Strand Breaks ◽  
Non Homologous End Joining ◽  
Eukaryotic Organisms

The NHEJ (non-homologous end-joining) pathway is one of the major mechanisms for repairing DSBs (double-strand breaks) that occur in genomic DNA. In common with eukaryotic organisms, many prokaryotes possess a conserved NHEJ apparatus that is essential for the repair of DSBs arising in the stationary phase of the cell cycle. Although the bacterial NHEJ complex is much more minimal than its eukaryotic counterpart, both pathways share a number of common mechanistic features. The relative simplicity of the prokaryotic NHEJ complex makes it a tractable model system for investigating the cellular and molecular mechanisms of DSB repair. The present review describes recent advances in our understanding of prokaryotic end-joining, focusing primarily on biochemical, structural and cellular aspects of the mycobacterial NHEJ repair pathway.

scholarly journals Single-Strand Annealing in Cancer

2021 ◽  
Vol 22 (4) ◽  
pp. 2167
Author(s):  
Janusz Blasiak
Keyword(s):  
Dna Repair ◽  
Synthetic Lethality ◽  
Single Strand ◽  
Repair System ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Cancer Pathogenesis ◽  
Single Strand Annealing ◽  
Non Homologous End Joining ◽  
Strand Annealing

DNA double-strand breaks (DSBs) are among the most serious forms of DNA damage. In humans, DSBs are repaired mainly by non-homologous end joining (NHEJ) and homologous recombination repair (HRR). Single-strand annealing (SSA), another DSB repair system, uses homologous repeats flanking a DSB to join DNA ends and is error-prone, as it removes DNA fragments between repeats along with one repeat. Many DNA deletions observed in cancer cells display homology at breakpoint junctions, suggesting the involvement of SSA. When multiple DSBs occur in different chromosomes, SSA may result in chromosomal translocations, essential in the pathogenesis of many cancers. Inhibition of RAD52 (RAD52 Homolog, DNA Repair Protein), the master regulator of SSA, results in decreased proliferation of BRCA1/2 (BRCA1/2 DNA Repair Associated)-deficient cells, occurring in many hereditary breast and ovarian cancer cases. Therefore, RAD52 may be targeted in synthetic lethality in cancer. SSA may modulate the response to platinum-based anticancer drugs and radiation. SSA may increase the efficacy of the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 (CRISPR associated 9) genome editing and reduce its off-target effect. Several basic problems associated with SSA, including its evolutionary role, interplay with HRR and NHEJ and should be addressed to better understand its role in cancer pathogenesis and therapy.

scholarly journals Nej1(XLF) inhibits Sae2(CTIP)-Dna2(DNA2) mediated resection at DNA double strand breaks

2021 ◽  
Author(s):  
Aditya Mojumdar ◽  
Nancy Adam ◽  
Jennifer A Cobb
Keyword(s):  
Synthetic Lethality ◽  
Nuclease Activity ◽  
Strand Break ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Genomic Deletions ◽  
Dna Double Strand Break ◽  
Break Site ◽  
Dna End Resection ◽  
Non Homologous End Joining

The two major pathways of DNA double strand break (DSB) repair, non-homologous end-joining (NHEJ) and homologous recombination (HR), are highly conserved from yeast to mammals. Regulated 5 DNA end resection is important for repair pathway choice and repair outcomes. Nej1 was first identified as a canonical NHEJ factor involved in stimulating the ligation of broken DNA ends and, more recently, it was shown to be important for DNA end-bridging and inhibiting Dna2-Sgs1 mediated 5 resection. Dna2 localizes to DSBs in the absence of Sgs1 through interactions with Mre11 and Sae2 and DNA damage sensitivity is greater in cells lacking Dna2 nuclease activity compared to sgs1∆ mutants. Dna2-Sae2 mediated 5 resection is down-regulated by Nej1, which itself interacts with Sae2. The resection defect of sae2∆ and the synthetic lethality of sae2∆ sgs1∆ are reversed by deletion of NEJ1 and dependent on Dna2 nuclease activity. Our work demonstrates the importance of Nej1 in inhibiting short-range resection at a DSB by Dna2-Sae2, a critical regulatory mechanism that prevents the formation of genomic deletions at the break site.

scholarly journals ATM deficiency promotes progression of CRPC by enhancing Warburg effect

2019 ◽  
Vol 26 (1) ◽  
pp. 59-71 ◽  
Author(s):  
Lingfan Xu ◽  
Enze Ma ◽  
Tao Zeng ◽  
Ruya Zhao ◽  
Yulei Tao ◽  
...  
Keyword(s):  
Dna Repair ◽  
Warburg Effect ◽  
Molecular Mechanisms ◽  
Synthetic Lethality ◽  
Aerobic Glycolysis ◽  
Parp Inhibitor ◽  
Strand Break ◽  
Parp Inhibitors ◽  
Castration Resistant Prostate Cancer ◽  
Glucose Flux

ATM is a well-known master regulator of double strand break (DSB) DNA repair and the defective DNA repair has been therapeutically exploited to develop PARP inhibitors based on the synthetic lethality strategy. ATM mutation is found with increased prevalence in advanced metastatic castration-resistant prostate cancer (mCRPC). However, the molecular mechanisms underlying ATM mutation-driving disease progression are still largely unknown. Here, we report that ATM mutation contributes to the CRPC progression through a metabolic rather than DNA repair mechanism. We showed that ATM deficiency generated by CRISPR/Cas9 editing promoted CRPC cell proliferation and xenograft tumor growth. ATM deficiency altered cellular metabolism and enhanced Warburg effect in CRPC cells. We demonstrated that ATM deficiency shunted the glucose flux to aerobic glycolysis by upregulating LDHA expression, which generated more lactate and produced less mitochondrial ROS to promote CRPC cell growth. Inhibition of LDHA by siRNA or inhibitor FX11 generated less lactate and accumulated more ROS in ATM-deficient CRPC cells and therefore potentiated the cell death of ATM-deficient CRPC cells. These findings suggest a new therapeutic strategy for ATM-mutant CRPC patients by targeting LDHA-mediated glycolysis metabolism, which might be effective for the PARP inhibitor resistant mCRPC tumors.

scholarly journals TP53 modulates radiotherapy fraction size sensitivity in normal and malignant cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Selvakumar Anbalagan ◽  
Cecilia Ström ◽  
Jessica A. Downs ◽  
Penny A. Jeggo ◽  
David McBay ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Tumour Cells ◽  
Malignant Cells ◽  
End Joining ◽  
Split Dose ◽  
Fraction Size ◽  
Increased Sensitivity ◽  
Breast And Prostate Cancer ◽  
Non Homologous End Joining ◽  
Sparing Effect

AbstractRecent clinical trials in breast and prostate cancer have established that fewer, larger daily doses (fractions) of radiotherapy are safe and effective, but these do not represent personalised dosing on a patient-by-patient basis. Understanding cell and molecular mechanisms determining fraction size sensitivity is essential to fully exploit this therapeutic variable for patient benefit. The hypothesis under test in this study is that fraction size sensitivity is dependent on the presence of wild-type (WT) p53 and intact non-homologous end-joining (NHEJ). Using single or split-doses of radiation in a range of normal and malignant cells, split-dose recovery was determined using colony-survival assays. Both normal and tumour cells with WT p53 demonstrated significant split-dose recovery, whereas Li-Fraumeni fibroblasts and tumour cells with defective G1/S checkpoint had a large S/G2 component and lost the sparing effect of smaller fractions. There was lack of split-dose recovery in NHEJ-deficient cells and DNA-PKcs inhibitor increased sensitivity to split-doses in glioma cells. Furthermore, siRNA knockdown of p53 in fibroblasts reduced split-dose recovery. In summary, cells defective in p53 are less sensitive to radiotherapy fraction size and lack of split-dose recovery in DNA ligase IV and DNA-PKcs mutant cells suggests the dependence of fraction size sensitivity on intact NHEJ.

Hyper-Active Non-Homologous End Joining Selects for Synthetic Lethality Resistant and Pathological Hematopoietic Stem Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5400-5400
Author(s):  
Wei Du ◽  
Surya Amarachintha ◽  
Wilson Andrew ◽  
Qishen Pang
Keyword(s):  
Conflicts Of Interest ◽  
Synthetic Lethality ◽  
Strand Break ◽  
Parp Inhibition ◽  
End Joining ◽  
Dsb Repair ◽  
Hematopoietic Stem ◽  
Cellular Processes ◽  
Stem And Progenitor Cells ◽  
Non Homologous End Joining

Abstract The prominent role of Fanconi anemia (FA) proteins involves homologous recombination (HR) repair. Poly[ADP-ribose] polymerase1 (PARP1) functions in multiple cellular processes including DNA repair and PARP inhibition is an emerging targeted therapy for cancer patients deficient in HR. Here we show that PARP1 activation in hematopoietic stem and progenitor cells (HSPCs) in response to genotoxic or oxidative stress attenuates HSPC exhaustion. Mechanistically, PARP1 controls the balance between HR and non-homologous end joining (NHEJ) in double strand break (DSB) repair by preventing excessive NHEJ. Disruption of the FA core complex skews PARP1 function in DSB repair and led to hyper-active NHEJ in Fanca-/- or Fancc-/- HSPCs. Re-expression of PARP1 rescues the hyper-active NHEJ phenotype in Brca1-/-Parp1-/- but less effective in Fanca-/-Parp1-/- cells. Inhibition of NHEJ prevents myeloid/erythroid pathologies associated with "synthetic lethality" and reduces human engraftment. Our results suggest that hyper-active NHEJ may select for "synthetic lethality" resistant and pathological HSPCs. Disclosures No relevant conflicts of interest to declare.

scholarly journals Oncogenic KRAS drives radioresistance through upregulation of NRF2-53BP1-mediated non-homologous end-joining repair

2021 ◽  
Author(s):  
Linlin Yang ◽  
Changxian Shen ◽  
Adriana Estrada-Bernal ◽  
Ryan Robb ◽  
Moumita Chatterjee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Kras Mutation ◽  
Molecular Mechanisms ◽  
Mitotic Catastrophe ◽  
End Joining ◽  
Kras Mutations ◽  
Activating Mutations ◽  
Colorectal Cancer Cell Lines ◽  
Damage Response ◽  
Non Homologous End Joining

Abstract KRAS-activating mutations are oncogenic drivers and are correlated with radioresistance of multiple cancers, including colorectal cancer, but the underlying precise molecular mechanisms remain elusive. Herein we model the radiosensitivity of isogenic HCT116 and SW48 colorectal cancer cell lines bearing wild-type or various mutant KRAS isoforms. We demonstrate that KRAS mutations indeed lead to radioresistance accompanied by reduced radiotherapy-induced mitotic catastrophe and an accelerated release from G2/M arrest. Moreover, KRAS mutations result in increased DNA damage response and upregulation of 53BP1 with associated increased non-homologous end-joining (NHEJ) repair. Remarkably, KRAS mutations lead to activation of NRF2 antioxidant signaling to increase 53BP1 gene transcription. Furthermore, genetic silencing or pharmacological inhibition of KRAS, NRF2 or 53BP1 attenuates KRAS mutation-induced radioresistance, especially in G1 phase cells. These findings reveal an important role for a KRAS-induced NRF2-53BP1 axis in the DNA repair and survival of KRAS-mutant tumor cells after radiotherapy, and indicate that targeting NRF2, 53BP1 or NHEJ may represent novel strategies to selectively abrogate KRAS mutation-mediated radioresistance.

scholarly journals Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Diana Zatreanu ◽  
Helen M. R. Robinson ◽  
Omar Alkhatib ◽  
Marie Boursier ◽  
Harry Finch ◽  
...  
Keyword(s):  
Dna Repair ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Repair Process ◽  
End Joining ◽  
Synthetic Lethal ◽  
Non Homologous End Joining ◽  
Inhibitor Resistance

AbstractTo identify approaches to target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight (MW), allosteric inhibitors of the polymerase function of DNA polymerase Polθ, including ART558. ART558 inhibits the major Polθ-mediated DNA repair process, Theta-Mediated End Joining, without targeting Non-Homologous End Joining. In addition, ART558 elicits DNA damage and synthetic lethality in BRCA1- or BRCA2-mutant tumour cells and enhances the effects of a PARP inhibitor. Genetic perturbation screening revealed that defects in the 53BP1/Shieldin complex, which cause PARP inhibitor resistance, result in in vitro and in vivo sensitivity to small molecule Polθ polymerase inhibitors. Mechanistically, ART558 increases biomarkers of single-stranded DNA and synthetic lethality in 53BP1-defective cells whilst the inhibition of DNA nucleases that promote end-resection reversed these effects, implicating these in the synthetic lethal mechanism-of-action. Taken together, these observations describe a drug class that elicits BRCA-gene synthetic lethality and PARP inhibitor synergy, as well as targeting a biomarker-defined mechanism of PARPi-resistance.

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