scholarly journals SMCHD1 Promotes ATM-dependent DNA Damage Signaling and Repair of Uncapped Telomeres

2019 ◽  
Author(s):  
Aleksandra Vančevska ◽  
Verena Pfeiffer ◽  
Marianna Feretzaki ◽  
Wareed Ahmed ◽  
Joachim Lingner
Keyword(s):  
Dna Damage ◽  
Time Course ◽  
End Joining ◽  
Checkpoint Signaling ◽  
Dna Damage Signaling ◽  
Damage Repair ◽  
Subsequent Activation ◽  
Non Homologous End Joining ◽  
Signaling Activation ◽  
Structural Maintenance Of Chromosomes

AbstractSMCHD1 (structural maintenance of chromosomes flexible hinge domain containing protein 1) has been implicated in X-chromosome inactivation, imprinting and DNA damage repair. Mutations in SMCHD1 can also cause facioscapulohumoral muscular dystrophy. More recently, SMCHD1 has also been detected as component of telomeric chromatin. Here, we identify requirements of SMCHD1 for DNA damage signaling and non-homologous end joining (NHEJ) at unprotected telomeres. Co-depletion of SMCHD1 with TRF2 reduced the rate of 3’ overhang removal in time course experiments and the number of telomere end fusions. In SMCHD1 deficient cells, the formation of ATM pS1981, γH2AX and 53BP1 containing telomere dysfunction induced foci (TIFs) were diminished indicating defects in checkpoint signaling. Strikingly, removal of TPP1 and subsequent activation of ATR signaling rescued telomere fusion events in TRF2-depleted SMCHD1 knockout cells. Together, these data indicate that SMCHD1 depletion reduces telomere fusions in TRF2-depleted cells due to defects in ATM-dependent DNA checkpoint signaling. SMCHD1 mediates DNA damage signaling activation upstream of ATM phosphorylation at uncapped telomeres.

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 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 Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors

2018 ◽  
Author(s):  
Manasi Ratnaparkhe ◽  
John Wong ◽  
Pei-Chi Wei ◽  
Mario Hlevnjak ◽  
Thorsten Kolb ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Genomic Rearrangements ◽  
End Joining ◽  
Catastrophic Events ◽  
Mouse Tumors ◽  
Damage Repair ◽  
Target Dna ◽  
Recombination Repair ◽  
Non Homologous End Joining

AbstractChromothripsis and chromoanasynthesis are catastrophic events leading to clustered genomic rearrangements. Whole-genome sequencing revealed frequent chromothripsis or chromoanasynthesis (n= 16/26) in brain tumors developing in mice deficient for factors involved in homologous-recombination-repair or non-homologous-end-joining. Catastrophic events were tightly linked to Myc/Mycn amplification, with increased DNA damage and inefficient apoptotic response already observable at early postnatal stages. Inhibition of repair processes and comparison of the mouse tumors with human medulloblastomas (n=68) and glioblastomas (n=32) identified chromothripsis as associated with MYC/MYCN gains and with DNA repair deficiencies, pointing towards therapeutic opportunities to target DNA repair defects in tumors with complex genomic rearrangements.

scholarly journals Withanolide D Enhances Radiosensitivity of Human Cancer Cells by Inhibiting DNA Damage Non-homologous End Joining Repair Pathway

2020 ◽  
Vol 9 ◽  
Author(s):  
Jerome Lacombe ◽  
Titouan Cretignier ◽  
Laetitia Meli ◽  
E. M. Kithsiri Wijeratne ◽  
Jean-Luc Veuthey ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Human Cancer ◽  
Repair Pathway ◽  
End Joining ◽  
Human Cancer Cells ◽  
Non Homologous End Joining

scholarly journals NBS1 is regulated by two kind of mechanisms: ATM-dependent complex formation with MRE11 and RAD50, and cell cycle–dependent degradation of protein

2017 ◽  
Vol 58 (4) ◽  
pp. 487-494 ◽  
Author(s):  
Hui Zhou ◽  
Kasumi Kawamura ◽  
Hiromi Yanagihara ◽  
Junya Kobayashi ◽  
Qiu-Mei Zhang-Akiyama
Keyword(s):  
Dna Damage ◽  
Complex Formation ◽  
Genetic Disorder ◽  
Specific Inhibitor ◽  
Nijmegen Breakage Syndrome ◽  
End Joining ◽  
Mrn Complex ◽  
Pre Treatment ◽  
Non Homologous End Joining ◽  
Cycle Dependent

Abstract Nijmegen breakage syndrome (NBS), a condition similar to Ataxia-Telangiectasia (A-T), is a radiation-hypersensitive genetic disorder showing chromosomal instability, radio-resistant DNA synthesis, immunodeficiency, and predisposition to malignances. The product of the responsible gene, NBS1, forms a complex with MRE11 and RAD50 (MRN complex). The MRN complex is necessary for the DNA damage–induced activation of ATM. However, the regulation of MRN complex formation is still unclear. Here, we investigated the regulatory mechanisms of MRN complex formation. We used an immunoprecipitation assay to determine whether levels of the MRN complex were increased by radiation-induced DNA damage and found that the levels of these proteins and their mRNAs did not increase. ATM-dependent phosphorylation of NBS1 contributed to the DNA damage–induced MRN complex formation. However, pre-treatment of cells with an ATM-specific inhibitor did not affect homologous recombination (HR) and non-homologous end-joining (NHEJ) repair. G0 phase cells, decreasing NBS1 and HR activity but not NHEJ, gained HR-related chromatin association of RAD51 by overexpression of NBS1, suggesting that the amount of NBS1 may be important for repressing accidental activation of HR. These evidences suggest that NBS1 is regulated by two kind of mechanisms: complex formation dependent on ATM, and protein degradation mediated by an unknown MG132-resistant pathway. Such regulation of NBS1 may contribute to cellular responses to double-strand breaks.

scholarly journals SIRT6 is a DNA double-strand break sensor

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Lior Onn ◽  
Miguel Portillo ◽  
Stefan Ilic ◽  
Gal Cleitman ◽  
Daniel Stein ◽  
...  
Keyword(s):  
Dna Damage ◽  
Binding Capacity ◽  
Critical Factor ◽  
Strand Break ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Downstream Signaling ◽  
The Road ◽  
Dna Double Strand Break ◽  
Non Homologous End Joining

DNA double-strand breaks (DSB) are the most deleterious type of DNA damage. In this work, we show that SIRT6 directly recognizes DNA damage through a tunnel-like structure that has high affinity for DSB. SIRT6 relocates to sites of damage independently of signaling and known sensors. It activates downstream signaling for DSB repair by triggering ATM recruitment, H2AX phosphorylation and the recruitment of proteins of the homologous recombination and non-homologous end joining pathways. Our findings indicate that SIRT6 plays a previously uncharacterized role as a DNA damage sensor, a critical factor in initiating the DNA damage response (DDR). Moreover, other Sirtuins share some DSB-binding capacity and DDR activation. SIRT6 activates the DDR before the repair pathway is chosen, and prevents genomic instability. Our findings place SIRT6 as a sensor of DSB, and pave the road to dissecting the contributions of distinct DSB sensors in downstream signaling.

Sign in / Sign up

Export Citation Format

Share Document