scholarly journals Oncogenes and the DNA Damage Response: Myc and E2F1 Engage the ATM Signaling Pathway to Activate p53 and Induce Apoptosis

Cell Cycle ◽  
2006 ◽  
Vol 5 (8) ◽  
pp. 801-803 ◽  
Author(s):  
Sungki Hong ◽  
Raju V. Pusapati ◽  
John T. Powers ◽  
David G. Johnson
Keyword(s):  
Dna Damage ◽  
Signaling Pathway ◽  
Dna Damage Response ◽  
Damage Response ◽  
Atm Signaling Pathway ◽  
Atm Signaling

scholarly journals INTS3 controls the hSSB1-mediated DNA damage response

2009 ◽  
Vol 187 (1) ◽  
pp. 25-32 ◽  
Author(s):  
Jeffrey R. Skaar ◽  
Derek J. Richard ◽  
Anita Saraf ◽  
Alfredo Toschi ◽  
Emma Bolderson ◽  
...  
Keyword(s):  
Dna Damage ◽  
Signaling Pathway ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
Binding Protein ◽  
Ataxia Telangiectasia Mutated ◽  
Uncharacterized Protein ◽  
Damage Response ◽  
Atm Signaling Pathway ◽  
Atm Signaling

Human SSB1 (single-stranded binding protein 1 [hSSB1]) was recently identified as a part of the ataxia telangiectasia mutated (ATM) signaling pathway. To investigate hSSB1 function, we performed tandem affinity purifications of hSSB1 mutants mimicking the unphosphorylated and ATM-phosphorylated states. Both hSSB1 mutants copurified a subset of Integrator complex subunits and the uncharacterized protein LOC58493/c9orf80 (henceforth minute INTS3/hSSB-associated element [MISE]). The INTS3–MISE–hSSB1 complex plays a key role in ATM activation and RAD51 recruitment to DNA damage foci during the response to genotoxic stresses. These effects on the DNA damage response are caused by the control of hSSB1 transcription via INTS3, demonstrating a new network controlling hSSB1 function.

scholarly journals Mutant huntingtin impairs PNKP and ATXN3, disrupting DNA repair and transcription

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Rui Gao ◽  
Anirban Chakraborty ◽  
Charlene Geater ◽  
Subrata Pradhan ◽  
Kara L Gordon ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Rna Polymerase Ii ◽  
Dna Damage Response ◽  
Functional Decline ◽  
Transcriptional Elongation ◽  
Damage Repair ◽  
Damage Response ◽  
Cyclic Amp Response Element ◽  
Atm Signaling

How huntingtin (HTT) triggers neurotoxicity in Huntington’s disease (HD) remains unclear. We report that HTT forms a transcription-coupled DNA repair (TCR) complex with RNA polymerase II subunit A (POLR2A), ataxin-3, the DNA repair enzyme polynucleotide-kinase-3'-phosphatase (PNKP), and cyclic AMP-response element-binding (CREB) protein (CBP). This complex senses and facilitates DNA damage repair during transcriptional elongation, but its functional integrity is impaired by mutant HTT. Abrogated PNKP activity results in persistent DNA break accumulation, preferentially in actively transcribed genes, and aberrant activation of DNA damage-response ataxia telangiectasia-mutated (ATM) signaling in HD transgenic mouse and cell models. A concomitant decrease in Ataxin-3 activity facilitates CBP ubiquitination and degradation, adversely impacting transcription and DNA repair. Increasing PNKP activity in mutant cells improves genome integrity and cell survival. These findings suggest a potential molecular mechanism of how mutant HTT activates DNA damage-response pro-degenerative pathways and impairs transcription, triggering neurotoxicity and functional decline in HD.

Crosstalk between Phosphoinositide 3‐kinase/Akt signaling pathway with DNA damage response and oxidative stress in cancer

2018 ◽  
Vol 120 (6) ◽  
pp. 10248-10272 ◽  
Author(s):  
Ansar Karimian ◽  
Sayed Mostafa Mir ◽  
Hadi Parsian ◽  
Sona Refieyan ◽  
Mohammad Mirza‐Aghazadeh‐Attari ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Signaling Pathway ◽  
Dna Damage Response ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Damage Response ◽  
Phosphoinositide 3 Kinase ◽  
And Oxidative Stress

scholarly journals IDH1R132H acts as a tumor suppressor in glioma via epigenetic upregulation of the DNA damage response

2018 ◽  
Author(s):  
Felipe J. Núñez ◽  
Flor M. Mendez ◽  
Padma Kadiyala ◽  
Mahmoud S. Alghamri ◽  
Masha G. Savelieff ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Tumor Suppressor ◽  
Dna Damage Response ◽  
Genomic Stability ◽  
Isocitrate Dehydrogenase 1 ◽  
Damage Response ◽  
Mutant Idh1 ◽  
Atm Signaling ◽  
The Impact

One sentence summaryMutant IDH1 acts as a tumor suppressor when co-expressed together with TP53 and ATRX inactivating mutations in glioma, inducing genomic stability, DNA repair and resistance to genotoxic therapies.AbstractGlioma patients whose tumors carry a mutation in the Isocitrate Dehydrogenase 1 (IDH1R132H) gene are younger at the time of diagnosis and survive longer. The molecular glioma subtype which we modelled, harbors IDH1R132H, tumor protein 53 (TP53) and alpha-thalassemia/mental retardation syndrome X-linked (ATRX) loss. The impact of IDH1R132H on genomic stability, DNA damage response (DDR) and DNA repair in this molecular glioma subtype is unknown. We discovered that IDH1R132H expression in the genetic context of ATRX and TP53 inactivation: (i) increases median survival (MS), (ii) enhances DDR activity via epigenetic upregulation of Ataxia-telangiectasia mutated (ATM) signaling, and (iii) elicits tumor radioresistance. Pharmacological inhibition of ATM or checkpoint kinase 1 and 2 (CHK1/2), two essential kinases in the DDR pathways, restored tumors’ radiosensitivity. Translation of these findings for mlDH1 glioma patients could significantly improve the therapeutic efficacy of radiotherapy, and thus have a major impact on patient survival.

scholarly journals Distinct versus overlapping functions of MDC1 and 53BP1 in DNA damage response and tumorigenesis

2008 ◽  
Vol 181 (5) ◽  
pp. 727-735 ◽  
Author(s):  
Katherine Minter-Dykhouse ◽  
Irene Ward ◽  
Michael S.Y. Huen ◽  
Junjie Chen ◽  
Zhenkun Lou
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Tumor Suppression ◽  
Cellular Response ◽  
Dna Double Strand Breaks ◽  
Ataxia Telangiectasia Mutated ◽  
Strand Breaks ◽  
Upstream Regulator ◽  
Damage Response ◽  
Atm Signaling

The importance of the DNA damage response (DDR) pathway in development, genomic stability, and tumor suppression is well recognized. Although 53BP1 and MDC1 have been recently identified as critical upstream mediators in the cellular response to DNA double-strand breaks, their relative hierarchy in the ataxia telangiectasia mutated (ATM) signaling cascade remains controversial. To investigate the divergent and potentially overlapping functions of MDC1 and 53BP1 in the ATM response pathway, we generated mice deficient for both genes. Unexpectedly, the loss of both MDC1 and 53BP1 neither significantly increases the severity of defects in DDR nor increases tumor incidence compared with the loss of MDC1 alone. We additionally show that MDC1 regulates 53BP1 foci formation and phosphorylation in response to DNA damage. These results suggest that MDC1 functions as an upstream regulator of 53BP1 in the DDR pathway and in tumor suppression.

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