scholarly journals WIP1 Promotes Homologous Recombination and Modulates Sensitivity to PARP Inhibitors

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1258 ◽  
Author(s):  
Kamila Burdova ◽  
Radka Storchova ◽  
Matous Palek ◽  
Libor Macurek
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Genotoxic Stress ◽  
Parp Inhibitors ◽  
Cell Cycle Checkpoint ◽  
Dna Lesion ◽  
Cycle Checkpoint ◽  
G2 Cells

Genotoxic stress triggers a combined action of DNA repair and cell cycle checkpoint pathways. Protein phosphatase 2C delta (referred to as WIP1) is involved in timely inactivation of DNA damage response by suppressing function of p53 and other targets at chromatin. Here we show that WIP1 promotes DNA repair through homologous recombination. Loss or inhibition of WIP1 delayed disappearance of the ionizing radiation-induced 53BP1 foci in S/G2 cells and promoted cell death. We identify breast cancer associated protein 1 (BRCA1) as interactor and substrate of WIP1 and demonstrate that WIP1 activity is needed for correct dynamics of BRCA1 recruitment to chromatin flanking the DNA lesion. In addition, WIP1 dephosphorylates 53BP1 at Threonine 543 that was previously implicated in mediating interaction with RIF1. Finally, we report that inhibition of WIP1 allowed accumulation of DNA damage in S/G2 cells and increased sensitivity of cancer cells to a poly-(ADP-ribose) polymerase inhibitor olaparib. We propose that inhibition of WIP1 may increase sensitivity of BRCA1-proficient cancer cells to olaparib.

scholarly journals Inhibition of DNA Repair in Cancer Therapy: Toward a Multi-Target Approach

2020 ◽  
Vol 21 (18) ◽  
pp. 6684
Author(s):  
Samuele Lodovichi ◽  
Tiziana Cervelli ◽  
Achille Pellicioli ◽  
Alvaro Galli
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Cancer Therapy ◽  
Clinical Outcome ◽  
Cancer Cells ◽  
Cell Cycle Checkpoint ◽  
Normal Cells ◽  
Cycle Checkpoint ◽  
Repair Pathways

Alterations in DNA repair pathways are one of the main drivers of cancer insurgence. Nevertheless, cancer cells are more susceptible to DNA damage than normal cells and they rely on specific functional repair pathways to survive. Thanks to advances in genome sequencing, we now have a better idea of which genes are mutated in specific cancers and this prompted the development of inhibitors targeting DNA repair players involved in pathways essential for cancer cells survival. Currently, the pivotal concept is that combining the inhibition of mechanisms on which cancer cells viability depends is the most promising way to treat tumorigenesis. Numerous inhibitors have been developed and for many of them, efficacy has been demonstrated either alone or in combination with chemo or radiotherapy. In this review, we will analyze the principal pathways involved in cell cycle checkpoint and DNA repair focusing on how their alterations could predispose to cancer, then we will explore the inhibitors developed or in development specifically targeting different proteins involved in each pathway, underscoring the rationale behind their usage and how their combination and/or exploitation as adjuvants to classic therapies could help in patients clinical outcome.

scholarly journals Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 750
Author(s):  
Kiyohiro Ando ◽  
Akira Nakagawara
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Progression ◽  
Parp Inhibitors ◽  
Cell Cycle Checkpoint ◽  
Mitotic Catastrophe ◽  
Malignant Neoplasms ◽  
Checkpoint Kinases ◽  
Molecular Features ◽  
Cycle Checkpoint

Unrestrained proliferation is a common feature of malignant neoplasms. Targeting the cell cycle is a therapeutic strategy to prevent unlimited cell division. Recently developed rationales for these selective inhibitors can be subdivided into two categories with antithetical functionality. One applies a “brake” to the cell cycle to halt cell proliferation, such as with inhibitors of cell cycle kinases. The other “accelerates” the cell cycle to initiate replication/mitotic catastrophe, such as with inhibitors of cell cycle checkpoint kinases. The fate of cell cycle progression or arrest is tightly regulated by the presence of tolerable or excessive DNA damage, respectively. This suggests that there is compatibility between inhibitors of DNA repair kinases, such as PARP inhibitors, and inhibitors of cell cycle checkpoint kinases. In the present review, we explore alterations to the cell cycle that are concomitant with altered DNA damage repair machinery in unfavorable neuroblastomas, with respect to their unique genomic and molecular features. We highlight the vulnerabilities of these alterations that are attributable to the features of each. Based on the assessment, we offer possible therapeutic approaches for personalized medicine, which are seemingly antithetical, but both are promising strategies for targeting the altered cell cycle in unfavorable neuroblastomas.

scholarly journals PARP Inhibitors as a Therapeutic Agent for Homologous Recombination Deficiency in Breast Cancers

2019 ◽  
Vol 8 (4) ◽  
pp. 435 ◽  
Author(s):  
Man Keung ◽  
Yanyuan Wu ◽  
Jaydutt Vadgama
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Predictive Biomarkers ◽  
Parp Inhibitors ◽  
Homologous Recombination Deficiency ◽  
Repair Pathways

Poly (ADP-ribose) polymerases (PARPs) play an important role in various cellular processes, such as replication, recombination, chromatin remodeling, and DNA repair. Emphasizing PARP’s role in facilitating DNA repair, the PARP pathway has been a target for cancer researchers in developing compounds which selectively target cancer cells and increase sensitivity of cancer cells to other anticancer agents, but which also leave normal cells unaffected. Since certain tumors (BRCA1/2 mutants) have deficient homologous recombination repair pathways, they depend on PARP-mediated base excision repair for survival. Thus, inhibition of PARP is a promising strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Although PARP inhibitor therapy has predominantly targeted BRCA-mutated cancers, this review also highlights the growing conversation around PARP inhibitor treatment for non-BRCA-mutant tumors, those which exhibit BRCAness and homologous recombination deficiency. We provide an update on the field’s progress by considering PARP inhibitor mechanisms, predictive biomarkers, and clinical trials of PARP inhibitors in development. Bringing light to these findings would provide a basis for expanding the use of PARP inhibitors beyond BRCA-mutant breast tumors.

scholarly journals Identification of Novel Biomarkers of Homologous Recombination Defect in DNA Repair to Predict Sensitivity of Prostate Cancer Cells to PARP-Inhibitors

2019 ◽  
Vol 20 (12) ◽  
pp. 3100 ◽  
Author(s):  
Daniela Criscuolo ◽  
Francesco Morra ◽  
Riccardo Giannella ◽  
Aniello Cerrato ◽  
Angela Celetti
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Synthetic Lethality ◽  
Parp Inhibitors ◽  
Androgen Deprivation ◽  
Prostate Cancer Cells ◽  
Castration Resistant ◽  
Novel Biomarkers

One of the most common malignancies in men is prostate cancer, for which androgen deprivation is the standard therapy. However, prostate cancer cells become insensitive to anti-androgen treatment and proceed to a castration-resistant state with limited therapeutic options. Therefore, besides the androgen deprivation approach, novel biomarkers are urgently required for specific targeting in this deadly disease. Recently, germline or somatic mutations in the homologous recombination (HR) DNA repair genes have been identified in at least 20–25% of metastatic castration-resistant prostate cancers (mCRPC). Defects in genes involved in HR DNA repair can sensitize cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors, a class of drugs already approved by the Food and Drug Administration (FDA) for breast and ovarian cancer carrying germline mutations in BRCA1/2 genes. For advanced prostate cancer carrying Breast cancer1/2 (BRCA1/2) or ataxia telengiectasia mutated (ATM) mutations, preclinical studies and clinical trials support the use of PARP-inhibitors, which received breakthrough therapy designation by the FDA. Based on these assumptions, several trials including DNA damage response and repair (DDR) targeting have been launched and are ongoing for prostate cancer. Here, we review the state-of-the-art potential biomarkers that could be predictive of cancer cell synthetic lethality with PARP inhibitors. The identification of key molecules that are affected in prostate cancer could be assayed in future clinical studies to better stratify prostate cancer patients who might benefit from target therapy.

scholarly journals Activated IGF-1R inhibits hyperglycemia-induced DNA damage and promotes DNA repair by homologous recombination

2005 ◽  
Vol 289 (5) ◽  
pp. F1144-F1152 ◽  
Author(s):  
Shuo Yang ◽  
Janaki Chintapalli ◽  
Lakshmi Sodagum ◽  
Stuart Baskin ◽  
Ashwani Malhotra ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Genomic Dna ◽  
Mesangial Cells ◽  
Reactive Oxygen ◽  
Genotoxic Stress ◽  
Ros Generation ◽  
Oxygen Intermediates ◽  
Strand Breaks

The IGF-1R is a genetic determinant of oxidative stress and longevity. Hyperglycemia induces an exponential increase in the production of a key danger signal, reactive oxygen intermediates, which target genomic DNA. Here, we report for the first time that ligand activation of the IGF-1R prevents hyperglycemia-induced genotoxic stress and enhances DNA repair, maintaining genomic integrity and cell viability. We performed single gel electrophoresis (comet assay) to evaluate DNA damage in serum-starved SV40 murine mesangial cells (MMC) and normal human mesangial cells (NHMC), maintained at high ambient glucose concentration. Hyperglycemia inflicted an impressive array of DNA damage in the form of single-strand breaks (SSBs) and double-strand breaks (DSBs). The inclusion of IGF-1 to culture media of MMC and NHMC prevented hyperglycemia-induced DNA damage. To determine whether DNA damage was mediated by reactive oxygen species (ROS), ROS generation was evaluated, in the presence of IGF-1, or the free radical scavenger n-acetyl-cysteine (NAC). IGF-1 and NAC inhibited hyperglycemic-induced ROS production and hyperglycemia-induced DNA damage. We next asked whether IGF-1 promotes the repair of DSB under hyperglycemic conditions, by homologous recombination (HRR) or nonhomologous end joining (NHEJ). Repair of DSB by NHEJ and HRR was operative in MMC maintained under hyperglycemic conditions. IGF-1 increased HRR by nearly twofold, whereas IGF-1 did not affect DNA repair by NHEJ. IGF-1R enhancement of HRR correlated with the translocation of Rad51 to foci of DNA damage. Inhibition of Rad51 expression by short interfering RNA experiments markedly decreased percentage of MMC positive for Rad51 nuclear foci and increased hyperglycemic DNA damage. We conclude that the activated IGF-1R rescues mesangial cells from hyperglycemia-induced danger signals that target genomic DNA by suppressing ROS and enhancing DNA repair by HRR.

scholarly journals Impaired homologous recombination DNA repair and enhanced sensitivity to DNA damage in prostate cancer cells exposed to anchorage-independence

Oncogene ◽  
2005 ◽  
Vol 24 (23) ◽  
pp. 3748-3758 ◽  
Author(s):  
Jin Ying Wang ◽  
Thu Ho ◽  
Joanna Trojanek ◽  
Janaki Chintapalli ◽  
Maja Grabacka ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Prostate Cancer Cells ◽  
Anchorage Independence ◽  
Enhanced Sensitivity

Spermidine/spermine N1-acetyltransferase overexpression in kidney epithelial cells disrupts polyamine homeostasis, leads to DNA damage, and causes G2 arrest

2007 ◽  
Vol 292 (3) ◽  
pp. C1204-C1215 ◽  
Author(s):  
Kamyar Zahedi ◽  
John J. Bissler ◽  
Zhaohui Wang ◽  
Anuradha Josyula ◽  
Lu Lu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Dna Damage ◽  
Dna Repair ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Dna Lesions ◽  
Cell Cycle Checkpoint ◽  
Cycle Checkpoint

Expression of spermidine/spermine N1-acetyltransferase (SSAT) increases in kidneys subjected to ischemia-reperfusion injury (IRI). Increased expression of SSAT in vitro leads to alterations in cellular polyamine content, depletion of cofactors and precursors of polyamine synthesis, and reduced cell proliferation. In our model system, a >28-fold increase in SSAT levels in HEK-293 cells leads to depletion of polyamines and elevation in the enzymatic activities of ornithine decarboxylase and S-adenosylmethionine decarboxylase, suggestive of a compensatory reaction to increased polyamine catabolism. Increased expression of SSAT also led to DNA damage and G2 arrest. The increased DNA damage was primarily due to the depletion of polyamines. Other factors such as increased production of H2O2 due to polyamine oxidase activity may play a secondary role in the induction of DNA lesions. In response to DNA damage the ATM/ATR → Chk1/2 DNA repair and cell cycle checkpoint pathways were activated, mediating the G2 arrest in SSAT-expressing cells. In addition, the activation of ERK1 and ERK2, which play integral roles in the G2/M transition, is impaired in cells expressing SSAT. These results indicate that the disruption of polyamine homeostasis due to enhanced SSAT activity leads to DNA damage and reduced cell proliferation via activation of DNA repair and cell cycle checkpoint and disruption of Raf → MEK → ERK pathways. We propose that in kidneys subjected to IRI, one mechanism through which increased expression of SSAT may cause cellular injury and organ damage is through induction of DNA damage and the disruption of cell cycle.

scholarly journals Molecularly targeting the PI3K-Akt-mTOR pathway can sensitize cancer cells to radiotherapy and chemotherapy

2014 ◽  
Vol 19 (2) ◽  
Author(s):  
Ziwen Wang ◽  
Yujung Huang ◽  
Jiqiang Zhang
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Mapk Signaling ◽  
Chemotherapeutic Agents ◽  
Cell Cycle Checkpoint ◽  
Mtor Signaling ◽  
Ras Signaling ◽  
Chemotherapy Drugs ◽  
Cycle Checkpoint

AbstractRadiotherapy and chemotherapeutic agents that damage DNA are the current major non-surgical means of treating cancer. However, many patients develop resistances to chemotherapy drugs in their later lives. The PI3K and Ras signaling pathways are deregulated in most cancers, so molecularly targeting PI3K-Akt or Ras-MAPK signaling sensitizes many cancer types to radiotherapy and chemotherapy, but the underlying molecular mechanisms have yet to be determined. During the multi-step processes of tumorigenesis, cancer cells gain the capability to disrupt the cell cycle checkpoint and increase the activity of CDK4/6 by disrupting the PI3K, Ras, p53, and Rb signaling circuits. Recent advances have demonstrated that PI3K-Akt-mTOR signaling controls FANCD2 and ribonucleotide reductase (RNR). FANCD2 plays an important role in the resistance of cells to DNA damage agents and the activation of DNA damage checkpoints, while RNR is critical for the completion of DNA replication and repair in response to DNA damage and replication stress. Regulation of FANCD2 and RNR suggests that cancer cells depend on PI3K-Akt-mTOR signaling for survival in response to DNA damage, indicating that the PI3K-AktmTOR pathway promotes resistance to chemotherapy and radiotherapy by enhancing DNA damage repair.

scholarly journals Genome maintenance functions of the INO80 chromatin remodeller

2017 ◽  
Vol 372 (1731) ◽  
pp. 20160289 ◽  
Author(s):  
Ashby J. Morrison
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Genome Stability ◽  
Chromatin Modification ◽  
Chromatin Remodelling ◽  
Cell Cycle Checkpoint ◽  
Post Translational Modification ◽  
Genome Maintenance ◽  
Cycle Checkpoint ◽  
Dna Damage Signalling

Chromatin modification is conserved in all eukaryotes and is required to facilitate and regulate DNA-templated processes. For example, chromatin manipulation, such as histone post-translational modification and nucleosome positioning, play critical roles in genome stability pathways. The INO80 chromatin-remodelling complex, which regulates the abundance and positioning of nucleosomes, is particularly important for proper execution of inducible responses to DNA damage. This review discusses the participation and activity of the INO80 complex in DNA repair and cell cycle checkpoint pathways, with emphasis on the Saccharomyces cerevisiae model system. Furthermore, the role of ATM/ATR kinases, central regulators of DNA damage signalling, in the regulation of INO80 function will be reviewed. In addition, emerging themes of chromatin remodelling in mitotic stability pathways and chromosome segregation will be introduced. These studies are critical to understanding the dynamic chromatin landscape that is rapidly and reversibly modified to maintain the integrity of the genome. This article is part of the themed issue ‘Chromatin modifiers and remodellers in DNA repair and signalling’.

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