scholarly journals SIRT1 inhibition impairs non-homologous end joining DNA damage repair by increasing Ku70 acetylation in chronic myeloid leukemia cells

Oncotarget ◽  
2015 ◽  
Vol 7 (12) ◽  
pp. 13538-13550 ◽  
Author(s):  
Wenjun Zhang ◽  
Haixia Wu ◽  
Meng Yang ◽  
Shiguang Ye ◽  
Liang Li ◽  
...  
Keyword(s):  
Dna Damage ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Dna Damage Repair ◽  
Leukemia Cells ◽  
End Joining ◽  
Damage Repair ◽  
Non Homologous End Joining

scholarly journals Integrated Stochastic Model of DNA Damage Repair by Non-homologous End Joining and p53/p21- Mediated Early Senescence Signalling

2015 ◽  
Vol 11 (5) ◽  
pp. e1004246 ◽  
Author(s):  
David W. P. Dolan ◽  
Anze Zupanic ◽  
Glyn Nelson ◽  
Philip Hall ◽  
Satomi Miwa ◽  
...  
Keyword(s):  
Dna Damage ◽  
Stochastic Model ◽  
Dna Damage Repair ◽  
End Joining ◽  
Damage Repair ◽  
Non Homologous End Joining

scholarly journals Blocking DNA Damage Repair May Be Involved in Stattic (STAT3 Inhibitor)-Induced FLT3-ITD AML Cell Apoptosis

2021 ◽  
Vol 9 ◽  
Author(s):  
Yuxuan Luo ◽  
Ying Lu ◽  
Bing Long ◽  
Yansi Lin ◽  
Yanling Yang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
Dna Damage Repair ◽  
Underlying Mechanism ◽  
Internal Tandem Duplication ◽  
Mrna Sequencing ◽  
Damage Repair ◽  
Flt3 Inhibitors ◽  
Flt3 Internal Tandem Duplication

The FMS-like tyrosine kinase 3 (FLT3)- internal tandem duplication (ITD) mutation can be found in approximately 25% of all acute myeloid leukemia (AML) cases and is associated with a poor prognosis. The main treatment for FLT3-ITD-positive AML patients includes genotoxic therapy and FLT3 inhibitors, which are rarely curative. Inhibiting STAT3 activity can improve the sensitivity of solid tumor cells to radiotherapy and chemotherapy. This study aimed to explore whether Stattic (a STAT3 inhibitor) affects FLT3-ITD AML cells and the underlying mechanism. Stattic can inhibit the proliferation, promote apoptosis, arrest cell cycle at G0/G1, and suppress DNA damage repair in MV4-11cells. During the process, through mRNA sequencing, we found that DNA damage repair-related mRNA are also altered during the process. In summary, the mechanism by which Stattic induces apoptosis in MV4-11cells may involve blocking DNA damage repair machineries.

scholarly journals 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

2018 ◽  
Vol 49 (6) ◽  
pp. 2111-2123 ◽  
Author(s):  
Wenlei Yu ◽  
Liang Li ◽  
Guangming Wang ◽  
Wenjun Zhang ◽  
Jun Xu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Jurkat Cells ◽  
Cell Leukemia ◽  
End Joining ◽  
Adult T Cell Leukemia ◽  
Damage Repair ◽  
Repair Efficiency ◽  
Promising Target ◽  
Non Homologous End Joining

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.

scholarly journals Ablating Ku70 phosphorylation results in defective DNA damage repair and spontaneous induction of hepatocellular carcinoma

2021 ◽  
Author(s):  
Janapriya Saha ◽  
Jinsung Bae ◽  
Shih-Ya Wang ◽  
Lori J. Chappell ◽  
Purva Gopal ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dna Damage ◽  
Genomic Instability ◽  
Dna Damage Repair ◽  
Strand Break ◽  
Damage Repair ◽  
Dna End Resection ◽  
Non Homologous End Joining ◽  
Transformed Cell Lines ◽  
Dna Ends

SUMMARYMultiple pathways mediate the repair of DNA double-strand break (DSB), with numerous mechanisms responsible for driving choice between the pathways. Previously, we reported that phosphorylation of the non-homologous end joining (NHEJ) factor, Ku70, is required for the dissociation of the Ku heterodimer from DNA ends to allow DSB repair via homologous recombination (HR). A knock-in mouse, in which phosphorylation is ablated in the three conserved sites of Ku70 (Ku703A/3A), was generated in order to test the hypothesis that Ku70 phosphorylation is required for initiation of HR and that blocking this process results in enhanced genomic instability and tumorigenesis. Here, we show that Ku703A/3A mice develop spontaneous and have accelerated chemical-induced hepatocellular carcinoma (HCC) compared to wild-type (Ku70+/+) littermates. The HCC tumors from the Ku703A/3A mice have increased γH2AX and 8-oxo-G staining, suggesting DNA repair is decreased in these mice. Spontaneous transformed cell lines from Ku703A/3A mice are more radiosensitive, have a significant decrease in DNA end resection, and are more sensitive to the DNA cross-linking agent mitomycin C compared to cells from Ku70+/+ littermates. Collectively, these findings demonstrate that phosphorylation-mediated dissociation of Ku heterodimer from DNA ends is required for efficient DNA damage repair and disruption of this process results in genomic instability and accelerated development of HCC.

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