The DNA damage response pathway in normal hematopoiesis and malignancies

Delia, Domenico; Mizutani, Shuki

doi:10.1007/s12185-017-2300-7

Cited by 44 publications

(33 citation statements)

References 57 publications

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“…HR appears the predominant mechanism of DDR in yeast, which is operative only in the S/G2 phases of the cell cycle. By contrast, NHEJ works in all phases of the cell cycle by binding together the broken DNA ends and is considered to be the major repair pathway of DSBs in mammalian cells [9,10].…”

Section: Introductionmentioning

confidence: 99%

KU70 Inhibition Impairs Both Non-Homologous End Joining and Homologous Recombination DNA Damage Repair Through SHP-1 Induced Dephosphorylation of SIRT1 in Adult T-Cell Leukemia-Lymphoma Cells

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Adult T-cell leukemia-lymphoma (ATL) is an aggressive disease which is highly resistant to chemotherapy. Studies show that enhanced ability of DNA damage repair (DDR) in cancer cells plays a key role in chemotherapy resistance. Here, we suggest that defect in DDR related genes might be a promising target to destroy the genome stability of tumor cells. Methods: Since KU70 is highly expressed in Jurkat cells, one of the most representative cell lines of ATL, we knocked down KU70 by shRNA and analyzed the impact of KU70 deficiency in Jurkat cells as well as in NOD-SCID animal models by western blot, immunofluorescence, flow cytometry and measuring DNA repair efficiency. Results: It is observed that silencing of KU70 resulted in accumulated DNA damage and impaired DDR in Jurkat cells, resulting in more apoptosis, decreased cell proliferation and cell cycle arrest. DNA damage leads to DNA double-strand breaks (DSBs), which are processed by either non-homologous end joining(NHEJ) or homologous recombination(HR). In our study, both NHEJ and HR are impaired because of KU70 defect, accompanied with increased protein level of SHP-1, a dephosphorylation enzyme. In turn, SHP-1 led to dephosphorylation of SIRT1, which further impaired HR repair efficiency. Moreover, KU70 deficiency prolonged survival of Jurkat-xenografted mice. Conclusion: These findings suggest that targeting KU70 is a promising target for ATL and might overcome the existing difficulties in chemotherapy.

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Section: Introductionmentioning

confidence: 99%

KU70 Inhibition Impairs Both Non-Homologous End Joining and Homologous Recombination DNA Damage Repair Through SHP-1 Induced Dephosphorylation of SIRT1 in Adult T-Cell Leukemia-Lymphoma Cells

Wang

et al. 2018

Cell Physiol Biochem

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“…The oxidative DNA damage caused by excessive intracellular levels of ROS triggers a variety of cell intrinsic antiproliferative and antitumor responses such as cell cycle arrest, cell senescence, and apoptosis [16]. To avoid the harmful effects of ROS, many tumors develop adaptive responses, including the upregulation of protective redox buffering systems [17], the activation of sanitization pathways that prevent the incorporation of damaged nucleotides into newly synthesized DNA [18], and the activation of DNA repair pathways such as nucleotide and base excision repair (NER and BER) that purge DNA from oxidated bases to restore nucleic acid integrity [19].…”

Section: Introductionmentioning

confidence: 99%

The Epstein–Barr virus nuclear antigen-1 upregulates the cellular antioxidant defense to enable B-cell growth transformation and immortalization

2019

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Epstein-Barr virus (EBV) immortalizes human B-lymphocytes and is implicated in the pathogenesis of lymphoid and epithelial cell malignancies. The EBV nuclear antigen (EBNA)-1 induces the accumulation of reactive oxygen species (ROS), which enables B-cell immortalization but causes oxidative DNA damage and triggers antiproliferative DNA damage responses. By comparing pairs of EBV-negative and-positive tumor cell lines we found that, while associated with the accumulation of oxidized nucleotides, EBV carriage promotes the concomitant activation of oxo-dNTP sanitization and purging pathways, including upregulation of the nucleoside triphosphatase mut-T homolog 1 (MTH1) and the DNA glycosylases 8-oxoguanine-glycosylase-1 (OGG1) and mut-Y homolog (MUTYH). Expression of EBNA1 was reversibly associated with transcriptional activation of this cellular response. DNA damage and apoptosis were preferentially induced in EBNA1-positive cell lines by treatment with MTH1 inhibitors, suggesting that virus carriage is linked to enhanced vulnerability to oxidative stress. MTH1, OGG1, and MUTYH were upregulated upon EBV infection in primary B-cells and treatment with MTH1 inhibitors prevented B-cell immortalization. These findings highlight an important role of the cellular antioxidant response in sustaining EBV infection, and suggests that targeting this cellular defense may offer a novel approach to antiviral therapy and could reduce the burden of EBV associated cancer.

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“…Therefore, DDR kinases targeting may represent a new strategy to reduce leukemic cell survival and to promote the selective elimination of the leukemic clone by inducing the differentiation and/or apoptosis of damaged cells. Compounds that inhibit the activity of specific DDR kinases generate DNA lesions that selectively kill cancer cells, which are generally characterized by defects in (i) DNA repair pathways, (ii) replication fork stress, (iii) genomic instability, and (iv) defective control of the cell cycle, in order to prevent the efficient repair of the DNA lesion . Targeting the replicative stress response by inhibiting the ATR‐CHK1 decreases the strength of cell cycle checkpoints and perturbs DNA replication process.…”

Section: Inhibitors Of Dna Damage Repair Kinases In Clinical Trials (mentioning

confidence: 99%

“…Targeting the replicative stress response by inhibiting the ATR‐CHK1 decreases the strength of cell cycle checkpoints and perturbs DNA replication process. Consequently, cells are more prone to enter into mitosis with high levels of DNA damage or under‐replicated DNA and undergo a process called “mitotic catastrophe” that leads to apoptosis . A number of studies support the notion that cancer cells are more sensitive to the loss of DDR functions compared to normal tissues .…”

Section: Inhibitors Of Dna Damage Repair Kinases In Clinical Trials (mentioning

confidence: 99%

“…These compounds are used alone and in combination with chemotherapy, radiotherapy, or other targeted therapeutics, including PARP inhibitors, PI3K/mTOR/AKT inhibitors, and immunotherapy drugs (Table ). Although preclinical data support the use of CHK1 and CHK2 inhibitors in the treatment of leukemias , only few studies were designed to assess their safety, tolerability, and pharmacokinetics in combination with chemotherapies (i.e., cytarabine and fludarabine) (Table ). A phase I trial in which the selective CHK1 inhibitor MK‐8776 (also named SCH‐900776) is combined with the prototypic antileukemic nucleoside analog cytarabine for the treatment of 24 adults with relapsed and refractory leukemias showed that this combination treatment induces disease remission in AMLs.…”

Section: Inhibitors Of Dna Damage Repair Kinases In Clinical Trials (mentioning

confidence: 99%

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Are DNA damage response kinases a target for the differentiation treatment of acute myeloid leukemia?

et al. 2018

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Acute myeloid leukemia (AML) is a genetically heterogeneous malignancy characterized by the expansion of hematopoietic stem/progenitor cells (HPCs) blocked at different stages of maturation/differentiation.The poor outcome of AMLs necessitates therapeutic improvement. In AML, genes encoding for myeloid transcription factors, signaling receptors regulating cell proliferation, and epigenetic modifiers can be mutated by somatically acquired genetic mutations or altered by chromosomal translocations. These mutations modify chromatin organization at genes sites regulating HPCs proliferation, terminal differentiation, and DNA repair, contributing to the development and progression of the disease. The reversibility of the epigenetic modifications by drug treatment makes epigenetic changes attractive targets for AML therapeutic intervention. Recent findings underline increased DNA damage and abnormalities in the DNA damage response (DDR) as a critical feature of AML blasts. The DDR preserves cell integrity and must be tightly coordinated with DNA methylation and chromatin remodeling to ensure the accessibility to the DNA of transcription factors and repair enzymes. A crucial role in these events is played by the ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related protein (ATR) kinases, which are hyperactive in AML. Based on these findings, we hypothesize the inhibition of DNA damage kinases as an alternative or complementary strategy for the differentiation treatment of AML as it leads to a reduced ability to repair the DNA damage, and to the inhibition of specific epigenetic modifiers whose function is altered in leukemic cells. © 2018 IUBMB Life, 70(11):-specific demethylase 1; MDC1, mediator of DNA damage checkpoint protein 1; MRN, MRE11/RAD50/NBN complex; PIKK, phosphatidylinositol 3-kinase-related kinase; PML, promyelocytic leukemia; PML-NB, PML-nuclear bodies; PML-RARα, promyelocytic leukemia-retinoic acid receptor α; RPA, replication protein A, SWI/SNF, switch/sucrose non-fermentable.

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The DNA damage response pathway in normal hematopoiesis and malignancies

Cited by 44 publications

References 57 publications

KU70 Inhibition Impairs Both Non-Homologous End Joining and Homologous Recombination DNA Damage Repair Through SHP-1 Induced Dephosphorylation of SIRT1 in Adult T-Cell Leukemia-Lymphoma Cells

KU70 Inhibition Impairs Both Non-Homologous End Joining and Homologous Recombination DNA Damage Repair Through SHP-1 Induced Dephosphorylation of SIRT1 in Adult T-Cell Leukemia-Lymphoma Cells

The Epstein–Barr virus nuclear antigen-1 upregulates the cellular antioxidant defense to enable B-cell growth transformation and immortalization

Are DNA damage response kinases a target for the differentiation treatment of acute myeloid leukemia?

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