DNA-PKcs-interacting protein KIP binding to TRF2 is required for the maintenance of functional telomeres

2014 ◽  
Vol 463 (1) ◽  
pp. 19-30 ◽  
Author(s):  
Prabhat Khadka ◽  
Ji Hoon Lee ◽  
Seung Han Baek ◽  
Sue Young Oh ◽  
In Kwon Chung
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Binding Activity ◽  
Interacting Protein ◽  
Damage Response

DNA-PKcs-interacting protein KIP interacts with TRF2 and enhances the telomere binding activity of TRF2. Depletion of KIP induces telomere-damage response foci. Thus KIP plays important roles in the maintenance of functional telomeres and the regulation of telomere-associated DNA-damage response.

scholarly journals Interplay between Mdm2 and HIPK2 in the DNA damage response

2014 ◽  
Vol 11 (96) ◽  
pp. 20140319 ◽  
Author(s):  
Xiao-Peng Zhang ◽  
Feng Liu ◽  
Wei Wang
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Negative Regulator ◽  
Critical Event ◽  
Apoptosis Induction ◽  
Nuclear Entry ◽  
Induce Cell Cycle Arrest ◽  
Interacting Protein ◽  
Cycle Arrest ◽  
Damage Response

The tumour suppressor p53 is activated to induce cell-cycle arrest or apoptosis in the DNA damage response (DDR). p53 phosphorylation at Ser46 by HIPK2 (homeodomain-interacting protein kinase 2) is a critical event in apoptosis induction. Interestingly, HIPK2 is degraded by Mdm2 (a negative regulator of p53), whereas Mdm2 is downregulated by HIPK2 through several mechanisms. Here, we develop a four-module network model for the p53 pathway to clarify the role of interplay between Mdm2 and HIPK2 in the DDR evoked by ultraviolet radiation. By numerical simulations, we reveal that Mdm2-dependent HIPK2 degradation promotes cell survival after mild DNA damage and that inhibition of HIPK2 degradation is sufficient to trigger apoptosis. In response to severe damage, p53 phosphorylation at Ser46 is promoted by the accumulation of HIPK2 due to downregulation of nuclear Mdm2 in the later phase of the response. Meanwhile, the concentration of p53 switches from moderate to high levels, contributing to apoptosis induction. We show that the presence of three mechanisms for Mdm2 downregulation, i.e. repression of mdm2 expression, inhibition of its nuclear entry and HIPK2-induced degradation, guarantees the apoptosis of irreparably damaged cells. Our results agree well with multiple experimental observations, and testable predictions are also made. This work advances our understanding of the regulation of p53 activity in the DDR and suggests that HIPK2 should be a significant target for cancer therapy.

scholarly journals Homeodomain-interacting protein kinase 2 regulates DNA damage response through interacting with heterochromatin protein 1γ

Oncogene ◽  
2014 ◽  
Vol 34 (26) ◽  
pp. 3463-3473 ◽  
Author(s):  
Y Akaike ◽  
Y Kuwano ◽  
K Nishida ◽  
K Kurokawa ◽  
K Kajita ◽  
...  
Keyword(s):  
Dna Damage ◽  
Protein Kinase ◽  
Dna Damage Response ◽  
Heterochromatin Protein ◽  
Interacting Protein ◽  
Damage Response

scholarly journals A DNA Damage Response Screen Identifies RHINO, a 9-1-1 and TopBP1 Interacting Protein Required for ATR Signaling

Science ◽  
2011 ◽  
Vol 332 (6035) ◽  
pp. 1313-1317 ◽  
Author(s):  
C. Cotta-Ramusino ◽  
E. R. McDonald ◽  
K. Hurov ◽  
M. E. Sowa ◽  
J. W. Harper ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Interacting Protein ◽  
Damage Response

scholarly journals TRAIP regulates DNA double-strand break-induced ATM activation

2021 ◽  
Author(s):  
Tobias Gleich ◽  
Manfredo Quadroni ◽  
Gökhan Yigit ◽  
Bernd Wollnik ◽  
Marcel Huber ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Hela Cells ◽  
Spindle Assembly Checkpoint ◽  
Strand Break ◽  
Dna Double Strand Breaks ◽  
Screening Assay ◽  
Interacting Protein ◽  
Damage Response ◽  
Non Homologous End Joining

DNA double-strand breaks (DSBs) affect cell survival and genomic integrity. They are repaired by a highly coordinated process called the DNA damage response. Here, we report that the ubiquitously expressed nucleolar E3 ubiquitin ligase TRAF-interacting protein (TRAIP), previously shown to regulate the spindle assembly checkpoint, has an essential role during the DNA damage response. A biotinylation proximity screening assay (BioID) identified Ku80, Ku70, SMARCA5 (SNF2H) and DNA-PKcs as novel TRAIP interactors. Co-immunoprecipitations demonstrated that the interaction of TRAIP with Ku80 was transiently increased while the one with SMARCA5 was strongly decreased after treatment of HeLa cells with neocarzinostatin (NCS). Treatment of fibroblasts from a microcephalic primordial dwarfism patient carrying a hypomorphic TRAIP mutation or shRNA-mediated knockdown of TRAIP in HeLa cells with NCS impaired the activation of ataxia-telangiectasia mutated (ATM), a protein kinase crucial for the DNA damage response. As consequence, the maintenance of γH2AX and Chk2-T68 phosphorylation, two downstream targets of ATM, was significantly abrogated after NCS-inflicted DSBs. DNA repair assays showed that TRAIP inhibits incorrect end utilization during non-homologous end joining. These observations highlight TRAIP as novel regulator of ATM activity in DNA damage signaling.

scholarly journals Structure analysis of FAAP24 reveals single-stranded DNA-binding activity and domain functions in DNA damage response

Cell Research ◽  
2013 ◽  
Vol 23 (10) ◽  
pp. 1215-1228 ◽  
Author(s):  
Yucai Wang ◽  
Xiao Han ◽  
Fangming Wu ◽  
Justin W Leung ◽  
Megan G Lowery ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Binding ◽  
Structure Analysis ◽  
Dna Damage Response ◽  
Binding Activity ◽  
Single Stranded Dna ◽  
Dna Binding Activity ◽  
Damage Response

scholarly journals Homeodomain-Interacting Protein Kinase-2: A Critical Regulator of the DNA Damage Response and the Epigenome

2016 ◽  
Vol 17 (10) ◽  
pp. 1638 ◽  
Author(s):  
Yuki Kuwano ◽  
Kensei Nishida ◽  
Yoko Akaike ◽  
Ken Kurokawa ◽  
Tatsuya Nishikawa ◽  
...  
Keyword(s):  
Dna Damage ◽  
Protein Kinase ◽  
Dna Damage Response ◽  
Interacting Protein ◽  
Damage Response
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