Evidence for a role for histone deacetylase 4 (HDAC4) in the DNA damage response

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.

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

Cell Death and Disease ◽

10.1038/s41419-020-2708-5 ◽

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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Role of histone deacetylase 2 in epigenetics and cellular senescence: implications in lung inflammaging and COPD

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00175.2012 ◽

2012 ◽

Vol 303 (7) ◽

pp. L557-L566 ◽

Cited By ~ 70

Author(s):

Hongwei Yao ◽

Irfan Rahman

Keyword(s):

Oxidative Stress ◽

Dna Damage ◽

Histone Deacetylase ◽

Dna Damage Response ◽

Cellular Senescence ◽

Premature Aging ◽

Epigenetic Mechanism ◽

Histone Deacetylase 2 ◽

Damage Response

Histone deacetylase 2 (HDAC2) is a class I histone deacetylase that regulates various cellular processes, such as cell cycle, senescence, proliferation, differentiation, development, apoptosis, and glucocorticoid function in inhibiting inflammatory response. HDAC2 has been shown to protect against DNA damage response and cellular senescence/premature aging via an epigenetic mechanism in response to oxidative stress. These phenomena are observed in patients with chronic obstructive pulmonary disease (COPD). HDAC2 is posttranslationally modified by oxidative/carbonyl stress imposed by cigarette smoke and oxidants, leading to its reduction via an ubiquitination-proteasome dependent degradation in lungs of patients with COPD. In this perspective, we have discussed the role of HDAC2 posttranslational modifications and its role in regulation of inflammation, histone/DNA epigenetic modifications, DNA damage response, and cellular senescence, particularly in inflammaging, and during the development of COPD. We have also discussed the potential directions for future translational research avenues in modulating lung inflammaging and cellular senescence based on epigenetic chromatin modifications in diseases associated with increased oxidative stress.

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Novel SIRT1 Agonists, SRT501 and SRT2183, Induce Expression of DNA Repair Genes and Apoptosis of Ph− Acute Lymphoblastic Leukemia Cells Alone and in Combination with the HDAC Inhibitor LBH589..

Blood ◽

10.1182/blood.v114.22.3083.3083 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3083-3083

Author(s):

Anna Scuto ◽

Mark Kirschbaum ◽

Jennifer M Cermak ◽

Peter Atadja ◽

Richard Jove

Keyword(s):

Dna Damage ◽

Acute Lymphoblastic Leukemia ◽

Histone Deacetylase ◽

Dna Damage Response ◽

Histone Deacetylase Inhibitors ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Growth Arrest ◽

Mrna Levels ◽

Damage Response

Abstract Abstract 3083 Poster Board III-20 Histone Deacetylase Inhibitors (HDACi) such as LBH589, which inhibit the zinc containing catalytic domain of HDAC of classes I, II, and IV, demonstrate activity against various malignancies, particularly lymphoid malignancies. SIRT1 is an NAD+ dependent class III histone deacetylase, which deacetylates histones as well as non-histone proteins and is not affected directly by HDACi such as LBH589. It remains controversial whether inhibition of SIRT1 or its activation is more efficacious in anticancer therapy. We have studied the activity of two novel SIRT1 activators, SRT501 and SRT2183, in Philadelphia chromosome negative acute lymphoblastic leukemia (ALL) cell lines. Both pre B (NALM-6, Reh) and T cell (MOLT-4) ALL lines were treated with either SRT501 or SRT2183, as well as in combination with LBH589 and evaluated for biological and gene expression responses. SRT501 induced growth arrest and apoptosis at doses ranging from 10-100 uM, with even the lowest doses inhibiting growth at 72 hours. SRT2183 is much more potent, with growth arrest and apoptosis induced at doses ranging from 1-20 uM. PCR array analysis revealed that SRT2183 treatment leads to increased mRNA levels of pro-apoptosis, growth arrest, and DNA damage response genes. We have previously demonstrated that the activity of LBH589 is mediated in part through upregulation or acetylation of proteins involved in the DNA damage response pathways. Quantitative real-time PCR confirms that the combination of LBH589 with SRT2183 leads to significantly higher expression of GADD45A and GADD45G than either agent alone. The combination of LBH589 plus SRT2183 showed enhanced inhibition of c-Myc protein levels, phosphorylation of H2A.X, and interestingly, increased acetylation of p53 (acetylation of p53 was not seen with SRT2183 alone). In summary, the novel SIRT1 activators SRT501 and SRT2183 show growth inhibitory and pro-apoptotic activity in Ph- ALL alone and enhanced activity in combination with LBH589. Clinical studies of these agents, particularly in combination with HDACi are warranted. Disclosures Kirschbaum: Novartis: Consultancy. Cermak:Sirtris: Employment. Atadja:Novartis: Employment.

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Abstract 5543: DNA damage response and anti-apoptotic proteins are predictors of histone deacetylase inhibitors-mediated radiosensitization of glioblastoma

10.1158/1538-7445.am2014-5543 ◽

2014 ◽

Author(s):

Lotte M. Berghauser Pont ◽

Jenneke Kloezeman ◽

Kishan Naipail ◽

Martin van den Bent ◽

Dik van Gent ◽

...

Keyword(s):

Dna Damage ◽

Histone Deacetylase ◽

Dna Damage Response ◽

Histone Deacetylase Inhibitors ◽

Damage Response ◽

Apoptotic Proteins

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Combination of the Histone Deacetylase Inhibitor Vorinostat and Dasatinib Increases Apoptosis in Bcr-abl+ Cells and Reverses Changes Associated with CML Progression.

Blood ◽

10.1182/blood.v108.11.2165.2165 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2165-2165

Author(s):

Leo Kretzner ◽

Anna Scuto ◽

Agnes Juhasz ◽

Richard Jove ◽

Yun Yen ◽

...

Keyword(s):

Dna Damage ◽

Histone Deacetylase ◽

Dna Damage Response ◽

Histone Deacetylase Inhibitors ◽

Fusion Gene ◽

Single Agent ◽

Chronic Phase ◽

Myelogenous Leukemia ◽

Advanced Phase ◽

Damage Response

Abstract Chronic myelogenous leukemia (CML) is associated with the bcr-abl fusion gene product, a constitutively active non-receptor tyrosine kinase driving cell division. The potent bcr-abl kinase inhibitor, dasatinib, is now FDA approved for imatinib-refractory patients, being active in most cases other than those with the T315I mutation. However, accelerated phase CML is typified by further genetic changes, including the suppression of various DNA damage response and apoptosis related proteins (Radich, et al PNAS 2006). Thus a novel approach which may reverse these changes, might provide better treatment of accelerated phase CML. A new class of agents targeting epigenetic processes, the histone deacetylase inhibitors (HDACi), is believed to act upon chromatin allowing re-expression of tumor suppressor genes believed to be closed off to transcription by the tumor in its effort to grow in an uncontrolled manner. We reasoned that adding an HDACi to dasatinib treatment of CML cells could promote re-expression of genes responding to genetic instability in these cells. To test this hypothesis we tested dasatinib (D) and the HDACi Vorinistat (V, suberoylanilide hydroxamic acid, SAHA) alone and in combination, using K562 cells. Apoptosis was measured by Annexin V staining after 48 hours. Apoptosis results: 1uM Vorinostat: 10%; 2 uM V: 16%. Dasatinib 0.5 nM: 28%, 1 nM D: 44% In combination, 1uM V + 0.5 nM D: 41%, 1 uM V + 1nM D: 64%, 2 uM V + 0.5 nM D: 65%, 2 uM V + 1 nM D: 67%, suggesting significant increase in apoptosis for the combination over either single agent treatment alone. We therefore began surveying panels of DNA damage- and apoptosis-related genes by means of RT-PCR. Studying the combination of 2 uM V + 1 nM D, we found increased expression of several proteins, including GADD45G and FANCG, both DNA damage response proteins suppressed in the progression to accelerated phase CML. Other proapoptotic proteins were increased such as MAP2K6, SEMA4A, BIK, and TNF superfamily members 7 and 25. This data suggests that the changes associated with progression from chronic phase to accelerated and blast crisis CML may be epigenetic in nature, and that these changes may be reversed by the combination of vorinostat and dasatinib. A clinical trial of dasatanib and vorinostat in advanced phase CML would be of value.

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

Experimental & Molecular Medicine ◽

10.3858/emm.2010.42.3.020 ◽

2010 ◽

Vol 42 (3) ◽

pp. 195 ◽

Cited By ~ 25

Author(s):

Eun Ryoung Jang ◽

Jae Duk Choi ◽

Mi Ae Park ◽

Gajin Jeong ◽

Hyeseong Cho ◽

...

Keyword(s):

Dna Damage ◽

Histone Deacetylase ◽

Dna Damage Response ◽

Histone Deacetylase Inhibition ◽

Damage Response

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Loss of Sin3/Rpd3 Histone Deacetylase Restores the DNA Damage Response in Checkpoint-Deficient Strains of Saccharomyces cerevisiae

Molecular and Cellular Biology ◽

10.1128/mcb.23.13.4522-4531.2003 ◽

2003 ◽

Vol 23 (13) ◽

pp. 4522-4531 ◽

Cited By ~ 39

Author(s):

Kenneth L. Scott ◽

Sharon E. Plon

Keyword(s):

Saccharomyces Cerevisiae ◽

Dna Damage ◽

Histone Deacetylase ◽

Dna Damage Response ◽

Uv Irradiation ◽

Spindle Checkpoint ◽

Dna Damage Checkpoint ◽

Checkpoint Pathway ◽

Damage Response ◽

Mutant Strains

ABSTRACT We previously reported that expression of the human forkhead/winged helix transcription factor, CHES1 (checkpoint suppressor 1; FOXN3), suppresses sensitivity to DNA damage and restores damage-induced G2/M arrest in checkpoint-deficient strains of Saccharomyces cerevisiae. We find that a functional glutathione S-transferase-Ches1 fusion protein binds in vivo to Sin3, a component of the S. cerevisiae Sin3/Rpd3 histone deacetylase complex. Checkpoint mutant strains with SIN3 deleted show increased resistance to UV irradiation, which is not further enhanced by CHES1 expression. Conversely, overexpression of SIN3 blocks the Ches1-mediated G2/M delay in response to DNA damage, which is consistent with Ches1 acting by inhibiting the Sin3/Rpd3 complex. Deletion of either SIN3 or RPD3 in rad9 or mec1 checkpoint mutant strains suppresses sensitivity to replication blocks and DNA damage resulting from Cdc9 ligase deficiency and UV irradiation. SIN3 or RPD3 deletions also restored G2/M arrest after DNA damage without concomitant Rad53 phosphorylation in mec1 mutant strains. This DNA damage response is absent in mad1 spindle checkpoint mutants. These data suggest that modulation of chromatin structure may regulate checkpoint responses in S. cerevisiae. Inhibition of histone deacetylation results in a DNA damage checkpoint response mediated by the spindle checkpoint pathway that compensates for loss of the primary DNA damage checkpoint pathway.

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