scholarly journals TIE2-mediated tyrosine phosphorylation of H4 regulates DNA damage response by recruiting ABL1

2016 ◽  
Vol 2 (4) ◽  
pp. e1501290 ◽  
Author(s):  
Mohammad B. Hossain ◽  
Rehnuma Shifat ◽  
David G. Johnson ◽  
Mark T. Bedford ◽  
Konrad R. Gabrusiewicz ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Tyrosine Phosphorylation ◽  
Genotoxic Stress ◽  
Nonhomologous End Joining ◽  
End Joining ◽  
Human Gliomas ◽  
Direct Signal ◽  
Damage Response ◽  
Core Histones

DNA repair pathways enable cancer cells to survive DNA damage induced after genotoxic therapies. Tyrosine kinase receptors (TKRs) have been reported as regulators of the DNA repair machinery. TIE2 is a TKR overexpressed in human gliomas at levels that correlate with the degree of increasing malignancy. Following ionizing radiation, TIE2 translocates to the nucleus, conferring cells with an enhanced nonhomologous end-joining mechanism of DNA repair that results in a radioresistant phenotype. Nuclear TIE2 binds to key components of DNA repair and phosphorylates H4 at tyrosine 51, which, in turn, is recognized by the proto-oncogene ABL1, indicating a role for nuclear TIE2 as a sensor for genotoxic stress by action as a histone modifier. H4Y51 constitutes the first tyrosine phosphorylation of core histones recognized by ABL1, defining this histone modification as a direct signal to couple genotoxic stress with the DNA repair machinery.

scholarly journals Congenital bone marrow failure in DNA-PKcs mutant mice associated with deficiencies in DNA repair

2011 ◽  
Vol 193 (2) ◽  
pp. 295-305 ◽  
Author(s):  
Shichuan Zhang ◽  
Hirohiko Yajima ◽  
HoangDinh Huynh ◽  
Junke Zheng ◽  
Elsa Callen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dna Damage ◽  
Dna Repair ◽  
Bone Marrow Failure ◽  
Genotoxic Stress ◽  
Nonhomologous End Joining ◽  
End Joining ◽  
Hematopoietic Stem ◽  
Dependent Protein ◽  
P53 Activation

The nonhomologous end-joining (NHEJ) pathway is essential for radioresistance and lymphocyte-specific V(D)J (variable [diversity] joining) recombination. Defects in NHEJ also impair hematopoietic stem cell (HSC) activity with age but do not affect the initial establishment of HSC reserves. In this paper, we report that, in contrast to deoxyribonucleic acid (DNA)–dependent protein kinase catalytic subunit (DNA-PKcs)–null mice, knockin mice with the DNA-PKcs3A/3A allele, which codes for three alanine substitutions at the mouse Thr2605 phosphorylation cluster, die prematurely because of congenital bone marrow failure. Impaired proliferation of DNA-PKcs3A/3A HSCs is caused by excessive DNA damage and p53-dependent apoptosis. In addition, increased apoptosis in the intestinal crypt and epidermal hyperpigmentation indicate the presence of elevated genotoxic stress and p53 activation. Analysis of embryonic fibroblasts further reveals that DNA-PKcs3A/3A cells are hypersensitive to DNA cross-linking agents and are defective in both homologous recombination and the Fanconi anemia DNA damage response pathways. We conclude that phosphorylation of DNA-PKcs is essential for the normal activation of multiple DNA repair pathways, which in turn is critical for the maintenance of diverse populations of tissue stem cells in mice.

scholarly journals Databases and Bioinformatics Tools for the Study of DNA Repair

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Kaja Milanowska ◽  
Kristian Rother ◽  
Janusz M. Bujnicki
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Excision Repair ◽  
Uv Light ◽  
Dna Lesions ◽  
Environmental Chemicals ◽  
Nonhomologous End Joining ◽  
End Joining ◽  
Repair Mechanisms ◽  
Base Excision

DNA is continuously exposed to many different damaging agents such as environmental chemicals, UV light, ionizing radiation, and reactive cellular metabolites. DNA lesions can result in different phenotypical consequences ranging from a number of diseases, including cancer, to cellular malfunction, cell death, or aging. To counteract the deleterious effects of DNA damage, cells have developed various repair systems, including biochemical pathways responsible for the removal of single-strand lesions such as base excision repair (BER) and nucleotide excision repair (NER) or specialized polymerases temporarily taking over lesion-arrested DNA polymerases during the S phase in translesion synthesis (TLS). There are also other mechanisms of DNA repair such as homologous recombination repair (HRR), nonhomologous end-joining repair (NHEJ), or DNA damage response system (DDR). This paper reviews bioinformatics resources specialized in disseminating information about DNA repair pathways, proteins involved in repair mechanisms, damaging agents, and DNA lesions.

scholarly journals Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joining

2010 ◽  
Vol 17 (9) ◽  
pp. 1144-1151 ◽  
Author(s):  
Kyle M Miller ◽  
Jorrit V Tjeertes ◽  
Julia Coates ◽  
Gaëlle Legube ◽  
Sophie E Polo ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Nonhomologous End Joining ◽  
End Joining ◽  
Damage Response

scholarly journals 53BP1 deficiency combined with telomere dysfunction activates ATR-dependent DNA damage response

2012 ◽  
Vol 197 (2) ◽  
pp. 283-300 ◽  
Author(s):  
Paula Martínez ◽  
Juana M. Flores ◽  
Maria A. Blasco
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
Nonhomologous End Joining ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Strand Breaks ◽  
Homology Directed Repair ◽  
Damage Response

TRF1 protects mammalian telomeres from fusion and fragility. Depletion of TRF1 leads to telomere fusions as well as accumulation of γ-H2AX foci and activation of both the ataxia telangiectasia mutated (ATM)– and the ataxia telangiectasia and Rad3 related (ATR)–mediated deoxyribonucleic acid (DNA) damage response (DDR) pathways. 53BP1, which is also present at dysfunctional telomeres, is a target of ATM that accumulates at DNA double-strand breaks and favors nonhomologous end-joining (NHEJ) repair over ATM-dependent resection and homology-directed repair (homologous recombination [HR]). To address the role of 53BP1 at dysfunctional telomeres, we generated mice lacking TRF1 and 53BP1. 53BP1 deficiency significantly rescued telomere fusions in mouse embryonic fibroblasts (MEFs) lacking TRF1, but they showed evidence of a switch from the NHEJ- to HR-mediated repair of uncapped telomeres. Concomitantly, double-mutant MEFs showed evidence of hyperactivation of the ATR-dependent DDR. In intact mice, combined 53BP1/TRF1 deficiency in stratified epithelia resulted in earlier onset of DNA damage and increased CHK1 phosphorylation during embryonic development, leading to aggravation of skin phenotypes.

scholarly journals Nonhomologous-End-Joining Factors Regulate DNA Repair Fidelity during Sleeping Beauty Element Transposition in Mammalian Cells

2003 ◽  
Vol 23 (23) ◽  
pp. 8505-8518 ◽  
Author(s):  
Stephen R. Yant ◽  
Mark A. Kay
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Mammalian Cells ◽  
Donor Site ◽  
Protective Role ◽  
Sleeping Beauty ◽  
Nonhomologous End Joining ◽  
Dna Breaks ◽  
End Joining ◽  
Transposon Insertion

ABSTRACT Herein, we report that the DNA-dependent protein kinase (DNA-PK) regulates the DNA damage introduced during Sleeping Beauty (SB) element excision and reinsertion in mammalian cells. Using both plasmid- and chromosome-based mobility assays, we analyzed the repair of transposase-induced double-stranded DNA breaks in cells deficient in either the DNA-binding subunit of DNA-PK (Ku) or its catalytic subunit (DNA-PKcs). We found that the free 3′ overhangs left after SB element excision were efficiently and accurately processed by the major Ku-dependent nonhomologous-end-joining pathway. Rejoining of broken DNA molecules in the absence of Ku resulted in extensive end degradation at the donor site and greatly increased the frequency of recombination with ectopic templates. Therefore, the major DNA-PK-dependent DNA damage response predominates over more-error-prone repair pathways and thereby facilitates high-fidelity DNA repair during transposon mobilization in mammalian cells. Although transposable elements were not found to be efficiently circularized after transposase-mediated excision, DNA-PK deficiency supported more-frequent transposase-mediated element insertion than was found in wild-type controls. We conclude that, based on its ability to regulate excision site junctional diversity and transposon insertion frequency, DNA-PK serves an important protective role during transpositional recombination in mammals.

scholarly journals The Intermediate Filament Synemin Regulates Non-Homologous End Joining in an ATM-Dependent Manner

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1717 ◽  
Author(s):  
Sara Sofia Deville ◽  
Anne Vehlow ◽  
Sarah Förster ◽  
Ellen Dickreuter ◽  
Kerstin Borgmann ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Response ◽  
Intermediate Filament ◽  
Intermediate Filament Protein ◽  
Dependent Manner ◽  
End Joining ◽  
Damage Response ◽  
Non Homologous End Joining ◽  
Filament Protein

The treatment resistance of cancer cells is a multifaceted process in which DNA repair emerged as a potential therapeutic target. DNA repair is predominantly conducted by nuclear events; yet, how extra-nuclear cues impact the DNA damage response is largely unknown. Here, using a high-throughput RNAi-based screen in three-dimensionally-grown cell cultures of head and neck squamous cell carcinoma (HNSCC), we identified novel focal adhesion proteins controlling DNA repair, including the intermediate filament protein, synemin. We demonstrate that synemin critically regulates the DNA damage response by non-homologous end joining repair. Mechanistically, synemin forms a protein complex with DNA-PKcs through its C-terminal tail domain for determining DNA repair processes upstream of this enzyme in an ATM-dependent manner. Our study discovers a critical function of the intermediate filament protein, synemin in the DNA damage response, fundamentally supporting the concept of cytoarchitectural elements as co-regulators of nuclear events.

scholarly journals Mutant huntingtin impairs Ku70-mediated DNA repair

2010 ◽  
Vol 189 (3) ◽  
pp. 425-443 ◽  
Author(s):  
Yasushi Enokido ◽  
Takuya Tamura ◽  
Hikaru Ito ◽  
Anup Arumughan ◽  
Akihiko Komuro ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Double Strand Breaks ◽  
Nonhomologous End Joining ◽  
Abnormal Behavior ◽  
Mutant Huntingtin ◽  
End Joining ◽  
Strand Breaks ◽  
Damage Repair ◽  
Dependent Protein

DNA repair defends against naturally occurring or disease-associated DNA damage during the long lifespan of neurons and is implicated in polyglutamine disease pathology. In this study, we report that mutant huntingtin (Htt) expression in neurons causes double-strand breaks (DSBs) of genomic DNA, and Htt further promotes DSBs by impairing DNA repair. We identify Ku70, a component of the DNA damage repair complex, as a mediator of the DNA repair dysfunction in mutant Htt–expressing neurons. Mutant Htt interacts with Ku70, impairs DNA-dependent protein kinase function in nonhomologous end joining, and consequently increases DSB accumulation. Expression of exogenous Ku70 rescues abnormal behavior and pathological phenotypes in the R6/2 mouse model of Huntington’s disease (HD). These results collectively suggest that Ku70 is a critical regulator of DNA damage in HD pathology.

scholarly journals p53 mRNA Metabolism Links with the DNA Damage Response

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1446
Author(s):  
Sivakumar Vadivel Vadivel Gnanasundram ◽  
Ondrej Bonczek ◽  
Lixiao Wang ◽  
Sa Chen ◽  
Robin Fahraeus
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Response ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Genotoxic Stress ◽  
Repair Processes ◽  
Damage Response ◽  
P53 Mrna

Human cells are subjected to continuous challenges by different genotoxic stress attacks. DNA damage leads to erroneous mutations, which can alter the function of oncogenes or tumor suppressors, resulting in cancer development. To circumvent this, cells activate the DNA damage response (DDR), which mainly involves cell cycle regulation and DNA repair processes. The tumor suppressor p53 plays a pivotal role in the DDR by halting the cell cycle and facilitating the DNA repair processes. Various pathways and factors participating in the detection and repair of DNA have been described, including scores of RNA-binding proteins (RBPs) and RNAs. It has become increasingly clear that p53’s role is multitasking, and p53 mRNA regulation plays a prominent part in the DDR. This review is aimed at covering the p53 RNA metabolism linked to the DDR and highlights the recent findings.

scholarly journals HPF1-dependent histone ADP-ribosylation triggers chromatin relaxation to promote the recruitment of repair factors at sites of DNA damage

2021 ◽  
Author(s):  
Rebecca Smith ◽  
Siham Zentout ◽  
Catherine Chapuis ◽  
Gyula Timinszky ◽  
Sebastien Huet
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Response ◽  
Dna Lesions ◽  
End Joining ◽  
Adp Ribosylation ◽  
Damage Response ◽  
Non Homologous End Joining ◽  
Chromatin Relaxation ◽  
The Impact

PARP1 activity is regulated by its cofactor HPF1. The binding of HPF1 on PARP1 controls the grafting of ADP-ribose moieties on serine residues of proteins nearby the DNA lesions, mainly PARP1 and histones. However, the impact of HPF1 on DNA repair regulated by PARP1 remains unclear. Here, we show that HPF1 controls both the number and the length of the ADP-ribose chains generated by PARP1 at DNA lesions. We demonstrate that HPF1-dependent histone ADP-ribosylation, rather than auto-modification of PARP1, triggers the rapid unfolding of the chromatin structure at the DNA damage sites and promotes the recruitment of the repair factors CHD4 and CHD7. Together with the observation that HPF1 contributes to efficient repair both by homologous recombination and non-homologous end joining, our findings highlight the key roles played by this PARP1 cofactor at early stages of the DNA damage response.

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