scholarly journals Bcl-2-associated transcription factor 1 Ser290 phosphorylation mediates DNA damage response and regulates radiosensitivity in gastric cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jia Liu ◽  
Jingyi Li ◽  
Zhao Sun ◽  
Yangmiao Duan ◽  
Fengqin Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Damage ◽  
Transcription Factor ◽  
Protein Phosphorylation ◽  
Dna Damage Response ◽  
High Resolution Mass Spectrometry ◽  
Gene Set Enrichment Analysis ◽  
Label Free ◽  
Damage Response ◽  
Transcription Factor 1

Abstract Background DNA damage response plays critical roles in tumor pathogenesis and radiotherapy resistance. Protein phosphorylation is a critical mechanism in regulation of DNA damage response; however, the key mediators for radiosensitivity in gastric cancer still needs further exploration. Methods A quick label-free phosphoproteomics using high-resolution mass spectrometry and an open search approach was applied to paired tumor and adjacent tissues from five patients with gastric cancer. The dysregulated phosphoproteins were identified and their associated-pathways analyzed using Gene Set Enrichment Analysis (GSEA). The mostly regulated phosphoproteins and their potential functions were validated by the specific antibodies against the phosphorylation sites. Specific protein phosphorylation was further analyzed by functional and clinical approaches. Results 832 gastric cancer-associated unique phosphorylated sites were identified, among which 25 were up- and 52 down-regulated. Markedly, the dysregulated phosphoproteins were primarily enriched in DNA-damage-response-associated pathways. Particularly, the phosphorylation of Bcl-2-associated transcription factor 1 (BCLAF1) at Ser290 was significantly upregulated in tumor. The upregulation of BCLAF1 Ser290 phosphorylation (pBCLAF1 (Ser290)) in tumor was confirmed by tissue microarray studies and further indicated in association with poor prognosis of gastric cancer patients. Eliminating the phosphorylation of BCLAF1 at Ser290 suppressed gastric cancer (GC) cell proliferation. Upregulation of pBCLAF1 (Ser290) was found in association with irradiation-induced γ-H2AX expression in the nucleus, leading to an increased DNA damage repair response, and a marked inhibition of irradiation-induced cancer cell apoptosis. Conclusions The phosphorylation of BCLAF1 at Ser290 is involved in the regulation of DNA damage response, indicating an important target for the resistance of radiotherapy.

scholarly journals Bcl-2-associated Transcription Factor 1 Phosphorylation Mediated DNA Damage Response in Gastric Cancer

2021 ◽  
Author(s):  
Jia Liu ◽  
Jingyi Li ◽  
Zhao Sun ◽  
Yangmiao Duan ◽  
Fengqin Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Damage ◽  
Transcription Factor ◽  
Protein Phosphorylation ◽  
Dna Damage Response ◽  
High Resolution Mass Spectrometry ◽  
Gene Set Enrichment Analysis ◽  
Label Free ◽  
Damage Response ◽  
Transcription Factor 1

Abstract Background: DNA damage response plays critical roles in tumor pathogenesis and radiotherapy resistance. Various cellular activities including the initiation and major steps DNA damage response are regulated by protein phosphorylation, whereas the molecular mechanism remains largely unknown. Methods: A quick label-free phosphoproteomics using high-resolution mass spectrometry and an open search approach was applied to paired tumor and adjacent tissues from five patients with gastric cancer. The dysregulated phosphoproteins were identified and their associated-pathways analyzed using Gene Set Enrichment Analysis (GSEA). The mostly regulated phosphoproteins and their potential functions were validated by the specific antibodies against the phosphorylation sites. Specific protein phosphorylation was further analyzed by functional and clinical approaches. Results: 832 gastric cancer-associated unique phosphorylated sites were identified, among which 25 were up- and 52 down-regulated. Markedly, the dysregulated phosphoproteins were primarily enriched in DNA-damage-response-associated pathways. Particularly, the phosphorylation of Bcl-2-associated transcription factor 1 (BCLAF1) at Ser290 was significantly upregulated in tumor. The upregulation of BCLAF1 Ser290 phosphorylation (pBCLAF1(Ser290)) in tumor was confirmed by tissue microarray studies and further indicated in association with poor prognosis of gastric cancer patients. Eliminating the phosphorylation of BCLAF1 at Ser290 suppressed gastric cancer (GC) cell proliferation. Upregulation of pBCLAF1(Ser290) was found in association with irradiation-induced γ-H2AX expression in the nucleus, leading to an increased DNA damage repair response, and a marked inhibition of irradiation-induced cancer cell apoptosis. Conclusions: The phosphorylation of BCLAF1 at Ser290 is involved in the regulation of DNA damage response, indicating an important target for the resistance of radiotherapy.

scholarly journals The Mef/Elf4 Transcription Factor Fine Tunes the DNA Damage Response

2011 ◽  
Vol 71 (14) ◽  
pp. 4857-4865 ◽  
Author(s):  
Goro Sashida ◽  
Narae Bae ◽  
Silvana Di Giandomenico ◽  
Takashi Asai ◽  
Nadia Gurvich ◽  
...  
Keyword(s):  
Dna Damage ◽  
Transcription Factor ◽  
Dna Damage Response ◽  
Damage Response

scholarly journals Alpha-6 integrin promotes radioresistance of glioblastoma by modulating DNA damage response and the transcription factor Zeb1

2018 ◽  
Vol 9 (9) ◽  
Author(s):  
Aline Kowalski-Chauvel ◽  
Anouchka Modesto ◽  
Valerie Gouaze-andersson ◽  
Laurent Baricault ◽  
Julia Gilhodes ◽  
...  
Keyword(s):  
Dna Damage ◽  
Transcription Factor ◽  
Dna Damage Response ◽  
Damage Response

scholarly journals 144P Clinical implication of DNA damage response gene in patients with stage II or III gastric cancer

2020 ◽  
Vol 31 ◽  
pp. S1297
Author(s):  
I.G. Hwang ◽  
S.E. Park ◽  
J.H. Choi ◽  
H.S. Kim ◽  
H.Y. Min ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Clinical Implication ◽  
Stage Ii ◽  
Response Gene ◽  
Damage Response

scholarly journals A ChIP–chip approach reveals a novel role for transcription factor IRF1 in the DNA damage response

2009 ◽  
Vol 37 (4) ◽  
pp. 1073-1085 ◽  
Author(s):  
Mattia Frontini ◽  
Meeraa Vijayakumar ◽  
Alexander Garvin ◽  
Nicole Clarke
Keyword(s):  
Dna Damage ◽  
Transcription Factor ◽  
Dna Damage Response ◽  
Damage Response ◽  
Chip Chip

scholarly journals Runx2 (Runt-Related Transcription Factor 2) Links the DNA Damage Response to Osteogenic Reprogramming and Apoptosis of Vascular Smooth Muscle Cells

2020 ◽  
Author(s):  
Andrew M. Cobb ◽  
Syabira Yusoff ◽  
Robert Hayward ◽  
Sadia Ahmad ◽  
Mengxi Sun ◽  
...  
Keyword(s):  
Dna Damage ◽  
Transcription Factor ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Dna Damage Response ◽  
Genotoxic Stress ◽  
Dna Damage Signaling ◽  
Damage Response ◽  
Related Transcription Factor ◽  
Osteogenic Gene

Objective: The development of ectopic vascular calcification is strongly linked with organismal aging, which is primarily caused by the accumulation of DNA damage over time. As Runx2 (Runt-related transcription factor 2) has been identified as a regulator of vascular smooth muscle cell osteogenic transition, a key component of vascular calcification, we examined the relationship between DNA damage and Runx2 activation. Approach and Results: We found genotoxic stress-stimulated Runx2 accumulation and transactivation of its osteogenic target genes, leading to enhanced calcification. Inhibition of DNA damage signaling attenuated this response. Runx2 localized to sites of DNA damage and participated in DNA repair by regulating phosphorylation events on histone H2AX, with exogenous expression of Runx2 resulting in unrepaired DNA damage and increased apoptosis. Mechanistically, Runx2 was PARylated in response to genotoxic stress, and inhibition of this modification disrupted its localization at DNA lesions and reduced its binding to osteogenic gene promoters. Conclusions: These data identify Runx2 as a novel component of the DNA damage response, coupling DNA damage signaling to both osteogenic gene transcription and apoptosis and providing a mechanism for accelerated mineralization in aging and chronic disease.

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