scholarly journals Histone deacetylase 4 interacts with 53BP1 to mediate the DNA damage response

2003 ◽  
Vol 160 (7) ◽  
pp. 1017-1027 ◽  
Author(s):  
Gary D. Kao ◽  
W. Gillies McKenna ◽  
Matthew G. Guenther ◽  
Ruth J. Muschel ◽  
Mitchell A. Lazar ◽  
...  
Keyword(s):  
Dna Damage ◽  
Histone Deacetylase ◽  
Cell Lines ◽  
Dna Damage Response ◽  
Lethal Dose ◽  
Cell Cycle Checkpoint ◽  
Dna Breaks ◽  
Damage Response ◽  
Cycle Checkpoint ◽  
Histone Deacetylase 4

Anumber of proteins are recruited to nuclear foci upon exposure to double-strand DNA damage, including 53BP1 and Rad51, but the precise role of these DNA damage–induced foci remain unclear. Here we show in a variety of human cell lines that histone deacetylase (HDAC) 4 is recruited to foci with kinetics similar to, and colocalizes with, 53BP1 after exposure to agents causing double-stranded DNA breaks. HDAC4 foci gradually disappeared in repair-proficient cells but persisted in repair-deficient cell lines or cells irradiated with a lethal dose, suggesting that resolution of HDAC4 foci is linked to repair. Silencing of HDAC4 via RNA interference surprisingly also decreased levels of 53BP1 protein, abrogated the DNA damage–induced G2 delay, and radiosensitized HeLa cells. Our combined results suggest that HDAC4 is a critical component of the DNA damage response pathway that acts through 53BP1 and perhaps contributes in maintaining the G2 cell cycle checkpoint.

scholarly journals Intersection of Two Checkpoints: Could Inhibiting the DNA Damage Response Checkpoint Rescue Immune Checkpoint-Refractory Cancer?

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3415
Author(s):  
Peter H. Goff ◽  
Rashmi Bhakuni ◽  
Thomas Pulliam ◽  
Jung Hyun Lee ◽  
Evan T. Hall ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Tumor Immunity ◽  
Immune Checkpoint ◽  
Ataxia Telangiectasia ◽  
Management Strategies ◽  
Adaptive Immune Response ◽  
Cell Cycle Checkpoint ◽  
Damage Response ◽  
Cycle Checkpoint

Metastatic cancers resistant to immunotherapy require novel management strategies. DNA damage response (DDR) proteins, including ATR (ataxia telangiectasia and Rad3-related), ATM (ataxia telangiectasia mutated) and DNA-PK (DNA-dependent protein kinase), have been promising therapeutic targets for decades. Specific, potent DDR inhibitors (DDRi) recently entered clinical trials. Surprisingly, preclinical studies have now indicated that DDRi may stimulate anti-tumor immunity to augment immunotherapy. The mechanisms governing how DDRi could promote anti-tumor immunity are not well understood; however, early evidence suggests that they can potentiate immunogenic cell death to recruit and activate antigen-presenting cells to prime an adaptive immune response. Merkel cell carcinoma (MCC) is well suited to test these concepts. It is inherently immunogenic as ~50% of patients with advanced MCC persistently benefit from immunotherapy, making MCC one of the most responsive solid tumors. As is typical of neuroendocrine cancers, dysfunction of p53 and Rb with upregulation of Myc leads to the very rapid growth of MCC. This suggests high replication stress and susceptibility to DDRi and DNA-damaging agents. Indeed, MCC tumors are particularly radiosensitive. Given its inherent immunogenicity, cell cycle checkpoint deficiencies and sensitivity to DNA damage, MCC may be ideal for testing whether targeting the intersection of the DDR checkpoint and the immune checkpoint could help patients with immunotherapy-refractory cancers.

scholarly journals Arabidopsis Casein Kinase 2 triggers Stem Cell Exhaustion under Al Toxicity and Phosphate Deficiency Through activation of the DNA Damage Response pathway

2020 ◽  
Author(s):  
Wei Pengliang ◽  
Manon Demulder ◽  
Pascale David ◽  
Thomas Eekhout ◽  
Kaoru Okamoto Yoshiyama ◽  
...  
Keyword(s):  
Dna Damage ◽  
Stem Cell ◽  
Dna Damage Response ◽  
Stem Cell Niche ◽  
Al Toxicity ◽  
Cell Cycle Checkpoint ◽  
Damage Response ◽  
Cycle Checkpoint ◽  
Cell Niche ◽  
Dna Damage Response Pathway

Aluminum (Al) toxicity and inorganic phosphate (Pi) limitation are widespread chronic abiotic and mutually enhancing stresses that profoundly affect crop yield. Both stresses cause a strong inhibition of root growth, resulting from a progressive exhaustion of the stem cell niche. Here, we report on a casein kinase 2 (CK2) inhibitor identified by its capability to maintain a functional root stem cell niche under Al toxic conditions. CK2 operates through phosphorylation of the cell cycle checkpoint activator SUPPRESSOR OF GAMMA RADIATION1 (SOG1), priming its activity under DNA-damaging conditions. In addition to yielding Al tolerance, CK2 and SOG1 inactivation prevents meristem exhaustion under Pi starvation, revealing the existence of a low Pi-induced cell cycle checkpoint that depends on the DNA damage activator ATAXIA-TELANGIECTASIA MUTATED. Overall, our data reveal an important physiological role for the plant DNA damage response pathway under agriculturally limiting growth conditions, opening new avenues to cope with Pi limitation.

Molecular characterization of collaborator of ARF (CARF) as a DNA damage response and cell cycle checkpoint regulatory protein

2014 ◽  
Vol 322 (2) ◽  
pp. 324-334 ◽  
Author(s):  
Rumani Singh ◽  
Rajkumar S. Kalra ◽  
Kamrul Hasan ◽  
Zeenia Kaul ◽  
Caroline T. Cheung ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Molecular Characterization ◽  
Dna Damage Response ◽  
Regulatory Protein ◽  
Cell Cycle Checkpoint ◽  
Damage Response ◽  
Cycle Checkpoint

scholarly journals Deciphering the Genetic Aberrations in DNA Damage Response Genes and Their Possible Association with HNSCC

2020 ◽  
pp. 156-169
Author(s):  
L. Akshayaa ◽  
A. S. Smiline Girija ◽  
A. Paramasivam ◽  
J. Vijayashree Priyadharsini
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Wide Spectrum ◽  
Survival Curve ◽  
Cell Cycle Checkpoint ◽  
Single Nucleotide Variants ◽  
Differential Expression Pattern ◽  
Damage Response ◽  
Cycle Checkpoint ◽  
High Level

Head and neck squamous cell carcinoma (HNSCC) includes carcinomas in the oral cavity, pharynx and larynx. It is considered as the sixth most common form of cancer in the world. Several studies have confirmed that smoking and alcohol consumption are the major risk factors for HNSCC. DNA damage response genes play an important role in the maintenance of the genome. Defects in cell cycle checkpoint and DNA repair mechanisms, such as mutation or abnormalities, may lead to the wide spectrum of human diseases. The present study employs databases and computational tools to identify the genetic abnormalities associated with DNA damage related genes which might have a direct or indirect association with HNSCC. The demographic details of HNSCC patients was obtained from The Cancer Gene Atlas (TCGA, Firehose Legacy) dataset hosted by the cBioportal database. The oncoprint data analysis revealed the highest frequency of gene alteration in the ATR gene (15%), followed by ATM, BRCA2 and CHEK2 (5%). Other genes showed less than 5% alteration. The gene expression profile of ATR gene revealed its differential expression pattern in different grades of tumor relative to normal samples. The survival curve analysis using Kaplan-Meier method revealed that a high level expression of the ATR gene leads to poor survival rate in the female HNSCC patients when compared to males. Thus the present study has identified gross and single nucleotide variants in the ATR gene which could have a putative role in the development of tumor. Further experimental research is required to confirm this association.

scholarly journals PAICS contributes to gastric carcinogenesis and participates in DNA damage response by interacting with histone deacetylase 1/2

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Nan Huang ◽  
Chang Xu ◽  
Liang Deng ◽  
Xue Li ◽  
Zhixuan Bian ◽  
...  
Keyword(s):  
Dna Damage ◽  
Histone Deacetylase ◽  
Dna Damage Response ◽  
De Novo ◽  
Dna Damage Repair ◽  
Histone Deacetylase 1 ◽  
Damage Repair ◽  
Damage Response

AbstractPhosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), an essential enzyme involved in de novo purine biosynthesis, is connected with formation of various tumors. However, the specific biological roles and related mechanisms of PAICS in gastric cancer (GC) remain unclear. In the present study, we identified for the first time that PAICS was significantly upregulated in GC and high expression of PAICS was correlated with poor prognosis of patients with GC. In addition, knockdown of PAICS significantly induced cell apoptosis, and inhibited GC cell growth both in vitro and in vivo. Mechanistic studies first found that PAICS was engaged in DNA damage response, and knockdown of PAICS in GC cell lines induced DNA damage and impaired DNA damage repair efficiency. Further explorations revealed that PAICS interacted with histone deacetylase HDAC1 and HDAC2, and PAICS deficiency decreased the expression of DAD51 and inhibited its recruitment to DNA damage sites by impairing HDAC1/2 deacetylase activity, eventually preventing DNA damage repair. Consistently, PAICS deficiency enhanced the sensitivity of GC cells to DNA damage agent, cisplatin (CDDP), both in vitro and in vivo. Altogether, our findings demonstrate that PAICS plays an oncogenic role in GC, which act as a novel diagnosis and prognostic biomarker for patients with GC.

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