Cancer Research and Treatment

Original Articles

Interactome Analysis Reveals that Heterochromatin Protein 1γ (HP1γ) Is Associated with the DNA Damage Response Pathway: Hongtae Kim, Jae Duk Choi, Byung-Gyu Kim, Ho Chul Kang, Jong-Soo Lee; Cancer Res Treat. 2016;48(1):322-333. Published online March 6, 2015; DOI: https://doi.org/10.4143/crt.2014.294

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Purpose
Heterochromatin protein 1γ (HP1γ) interacts with chromosomes by binding to lysine 9-methylated histone H3 or DNA/RNA. HP1γ is involved in various biological processes. The purpose of this study is to gain an understanding of how HP1γ functions in these processes by identifying HP1γ-binding proteins using mass spectrometry.
Materials and Methods
We performed affinity purification of HP1γ-binding proteins using G1/S phase or prometaphase HEK293T cell lysates that transiently express mock or FLAG-HP1γ. Coomassie staining was performed for HP1γ-binding complexes, using cell lysates prepared by affinity chromatography FLAG-agarose beads, and the bands were digested and then analyzed using a mass spectrometry.
Results
We identified 99 HP1γ-binding proteins with diverse cellular functions, including spliceosome, regulation of the actin cytoskeleton, tight junction, pathogenic Escherichia coli infection, mammalian target of rapamycin signaling pathway, nucleotide excision repair, DNA replication, homologous recombination, and mismatch repair.
Conclusion
Our results suggested that HP1γ is functionally active in DNA damage response via proteinprotein interaction.

Citations

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Discovery, expression, cellular localization, and molecular properties of a novel, alternative spliced HP1γ isoform, lacking the chromoshadow domain
Angela Mathison, Thiago Milech De Assuncao, Nikita R. Dsouza, Monique Williams, Michael T. Zimmermann, Raul Urrutia, Gwen Lomberk, Albert Jeltsch
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CBX3 Promotes Gastric Cancer Progression and Affects Factors Related to Immunotherapeutic Responses

Hexin Lin, Jiabian Lian, Lu Xia, Guoxian Guan, Jun You
Cancer Management and Research.2020; Volume 12: 10113. CrossRef
Cbx3 inhibits vascular smooth muscle cell proliferation, migration, and neointima formation
Cheng Zhang, Dan Chen, Eithne Margaret Maguire, Shiping He, Jiangyong Chen, Weiwei An, Mei Yang, Tayyab Adeel Afzal, Le Anh Luong, Li Zhang, Han Lei, Qingchen Wu, Qingzhong Xiao
Cardiovascular Research.2018; 114(3): 443. CrossRef

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Activation of ATM-dependent DNA Damage Signal Pathway by a Histone Deacetylase Inhibitor, Trichostatin A: Jong-Soo Lee; Cancer Res Treat. 2007;39(3):125-130. Published online September 30, 2007; DOI: https://doi.org/10.4143/crt.2007.39.3.125

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Purpose

Ataxia-telangiectasia mutated (ATM) kinase regulates diverse cellular DNA damage responses, including genome surveillance, cell growth, and gene expression. While the role of histone acetylation/deacetylation in gene expression is well established, little is known as to whether this modification can activate an ATM-dependent signal pathway, and whether this modification can thereby be implicated in an ATM-mediated DNA damage response.

Materials and Methods

Formation of H2AXγ foci was examined in HeLa and U₂OS cells following treatment with a histone deacetylase inhibitor, Trichostatin A (TSA). We determine an ATM-dependency of the TSA-induced DNA damage signal pathway using isogenic A-T (ATM^-) and control (ATM⁺) cells. We monitored the phosphorylation of ATM, an ATM-downstream effector kinase, Chk2, and H2AXγ to detect the activation of the ATM-de pendent DNA damage signal pathway.

Results

Exposure of cells to TSA results in the formation of H2AXγ foci in HeLa and U₂OS cells. The TSA-induced formation of H2AXγ foci occurs in an ATM-dependent manner. TSA induces phosphorylation of serine 1981 of ATM, accumulation of phosphorylated H2AX and Chk2, and formation of H2AX foci, in a manner analogous to genotoxic DNA damage.

Conclusion

In this work, we show that TSA induces a DNA damage signaling pathway in an ATM-dependent manner. These results suggest that ATM can respond to altered histone acetylation induced by the histone deacetylase inhibitor, TSA.

Citations

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ATM modulates transcription in response to histone deacetylase inhibition as part of its DNA damage response
Eun Ryoung Jang, Jae Duk Choi, Mi Ae Park, Gajin Jeong, Hyeseong Cho, Jong-Soo Lee
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Functional Link between DNA Damage Responses and Transcriptional Regulation by ATM in Response to a Histone Deacetylase Inhibitor TSA: Jong-Soo Lee; Cancer Res Treat. 2007;39(3):116-124. Published online September 30, 2007; DOI: https://doi.org/10.4143/crt.2007.39.3.116

Abstract PDF PubReader ePub

Purpose

Mutations in the ATM (ataxia-telangiectasia mutated) gene, which encodes a 370 kd protein with a kinase catalytic domain, predisposes people to cancers, and these mutations are also linked to ataxia-telangiectasia (A-T). The histone acetylaion/deacetylation- dependent chromatin remodeling can activate the ATM kinase-mediated DNA damage signal pathway (in an accompanying work, Lee, 2007). This has led us to study whether this modification can impinge on the ATM-mediated DNA damage response via transcriptional modulation in order to understand the function of ATM in the regulation of gene transcription.

Materials and Methods

To identify the genes whose expression is regulated by ATM in response to histone deaceylase (HDAC) inhibition, we performed an analysis of oligonucleotide microarrays with using the appropriate cell lines, isogenic A-T (ATM^-) and control (ATM⁺) cells, following treatment with a HDAC inhibitor TSA.

Results

Treatment with TSA reprograms the differential gene expression profile in response to HDAC inhibition in ATM^- cells and ATM⁺ cells. We analyzed the genes that are regulated by TSA in the ATM-dependent manner, and we classified these genes into different functional categories, including those involved in cell cycle/DNA replication, DNA repair, apoptosis, growth/differentiation, cell- cell adhesion, signal transduction, metabolism and transcription.

Conclusions

We found that while some genes are regulated by TSA without regard to ATM, the patterns of gene regulation are differentially regulated in an ATM-dependent manner. Taken together, these finding indicate that ATM can regulate the transcription of genes that play critical roles in the molecular response to DNA damage, and this response is modulated through an altered HDAC inhibition-mediated gene expression.

Citations

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ATM modulates transcription in response to histone deacetylase inhibition as part of its DNA damage response
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Review Article

DNA Damage Response Mediated through BRCA1: Eun Ryoung Jang, Jong-Soo Lee; Cancer Res Treat. 2004;36(4):214-221. Published online August 31, 2004; DOI: https://doi.org/10.4143/crt.2004.36.4.214

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