HDAC1 deregulation promotes neuronal loss and deficit of motor function in stroke pathogenesis

AbstractStroke is a common cause of death worldwide and leads to disability and cognitive dysfunction. Ischemic stroke and hemorrhagic stroke are major categories of stroke, accounting for 68% and 32% of strokes, respectively. Each year, 15 million people experience stroke worldwide, and the stroke incidence is rising. Epigenetic modifications regulate gene transcription and play a major role in stroke. Accordingly, histone deacetylase 1 (HDAC1) participates in DNA damage repair and cell survival. However, the mechanisms underlying the role of HDAC1 in stroke pathogenesis are still controversial. Therefore, we investigated the role of HDAC1 in stroke by using a rat model of endothelin-1-induced brain ischemia. Our results revealed that HDAC1 was deregulated following stroke, and its expressional level and enzymatic activity were decreased. We also used MS-275 to inhibit HDAC1 function in rats exposed to ischemic insult. We found that HDAC1 inhibition promoted the infarct volume, neuronal loss, DNA damage, neuronal apoptosis after stroke, and levels of reactive oxygen species and inflammation cytokines. Additionally, HDAC1 inhibition deteriorated the behavioral outcomes of rats with ischemic insult. Overall, our findings demonstrate that HDAC1 participates in ischemic pathogenesis in the brain and possesses potential for use as a therapeutic target.

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LINC-PINT impedes DNA repair and enhances radiotherapeutic response by targeting DNA-PKcs in nasopharyngeal cancer

Cell Death and Disease ◽

10.1038/s41419-021-03728-2 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

You-hong Wang ◽

Zhen Guo ◽

Liang An ◽

Yong Zhou ◽

Heng Xu ◽

...

Keyword(s):

Dna Damage ◽

Nasopharyngeal Cancer ◽

Noncoding Rnas ◽

Dependent Protein Kinase ◽

Damage Repair ◽

Dependent Protein ◽

Cancer Tissues

AbstractRadioresistance continues to be the leading cause of recurrence and metastasis in nasopharyngeal cancer. Long noncoding RNAs are emerging as regulators of DNA damage and radioresistance. LINC-PINT was originally identified as a tumor suppressor in various cancers. In this study, LINC-PINT was significantly downregulated in nasopharyngeal cancer tissues than in rhinitis tissues, and low LINC-PINT expressions showed poorer prognosis in patients who received radiotherapy. We further identified a functional role of LINC-PINT in inhibiting the malignant phenotypes and sensitizing cancer cells to irradiation in vitro and in vivo. Mechanistically, LINC-PINT was responsive to DNA damage, inhibiting DNA damage repair through ATM/ATR-Chk1/Chk2 signaling pathways. Moreover, LINC-PINT increased radiosensitivity by interacting with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and negatively regulated the expression and recruitment of DNA-PKcs. Therefore, these findings collectively support the possibility that LINC-PINT serves as an attractive target to overcome radioresistance in NPC.

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PARP Power: A Structural Perspective on PARP1, PARP2, and PARP3 in DNA Damage Repair and Nucleosome Remodelling

International Journal of Molecular Sciences ◽

10.3390/ijms22105112 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5112

Author(s):

Lotte van Beek ◽

Éilís McClay ◽

Saleha Patel ◽

Marianne Schimpl ◽

Laura Spagnolo ◽

...

Keyword(s):

Dna Damage ◽

Dna Binding ◽

Parp Inhibitors ◽

Covalent Modification ◽

Activation Mechanism ◽

Cancer Therapies ◽

Damage Repair ◽

Complementary Role ◽

Functional Understanding

Poly (ADP-ribose) polymerases (PARP) 1-3 are well-known multi-domain enzymes, catalysing the covalent modification of proteins, DNA, and themselves. They attach mono- or poly-ADP-ribose to targets using NAD+ as a substrate. Poly-ADP-ribosylation (PARylation) is central to the important functions of PARP enzymes in the DNA damage response and nucleosome remodelling. Activation of PARP happens through DNA binding via zinc fingers and/or the WGR domain. Modulation of their activity using PARP inhibitors occupying the NAD+ binding site has proven successful in cancer therapies. For decades, studies set out to elucidate their full-length molecular structure and activation mechanism. In the last five years, significant advances have progressed the structural and functional understanding of PARP1-3, such as understanding allosteric activation via inter-domain contacts, how PARP senses damaged DNA in the crowded nucleus, and the complementary role of histone PARylation factor 1 in modulating the active site of PARP. Here, we review these advances together with the versatility of PARP domains involved in DNA binding, the targets and shape of PARylation and the role of PARPs in nucleosome remodelling.

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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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Metabolomics Reveals Aging-associated Attenuation of Noninvasive Radiation Biomarkers in Mice: Potential Role of Polyamine Catabolism and Incoherent DNA Damage-repair

Journal of Proteome Research ◽

10.1021/pr400161k ◽

2013 ◽

Vol 12 (5) ◽

pp. 2269-2281 ◽

Cited By ~ 23

Author(s):

Soumen K. Manna ◽

Kristopher W. Krausz ◽

Jessica A. Bonzo ◽

Jeffrey R. Idle ◽

Frank J. Gonzalez

Keyword(s):

Dna Damage ◽

Potential Role ◽

Dna Damage Repair ◽

Polyamine Catabolism ◽

Damage Repair

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Investigating the Role of SF3B1 Mutations in DNA Damage Repair in Myeloid Malignancies

Leukemia Research ◽

10.1016/s0145-2126(17)30391-0 ◽

2017 ◽

Vol 55 ◽

pp. S159-S160

Author(s):

K. Lappin ◽

F. Liberante ◽

K. Savage ◽

K. Mills

Keyword(s):

Dna Damage ◽

Dna Damage Repair ◽

Myeloid Malignancies ◽

Damage Repair

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Abstract 2039: The role of HORMAD1 in DNA damage repair in squamous cell carcinomas

10.1158/1538-7445.am2021-2039 ◽

2021 ◽

Author(s):

Jennifer Gantchev ◽

Amelia Martinez Villarreal ◽

Brandon Ramchatesingh ◽

Ivan V. Litvinov

Keyword(s):

Dna Damage ◽

Squamous Cell ◽

Dna Damage Repair ◽

Squamous Cell Carcinomas ◽

Damage Repair

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Modulator of apoptosis-1 is a potential therapeutic target in acute ischemic injury

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x18794839 ◽

2018 ◽

Vol 39 (12) ◽

pp. 2406-2418 ◽

Cited By ~ 3

Author(s):

Su Jing Chan ◽

Hui Zhao ◽

Kazuhide Hayakawa ◽

Chou Chai ◽

Chong Teik Tan ◽

...

Keyword(s):

Cortical Neurons ◽

Infarct Volume ◽

Neuronal Loss ◽

Ischemic Injury ◽

Glucose Deprivation ◽

Artery Occlusion ◽

In Vivo Models ◽

The Brain

Modulator of apoptosis 1 (MOAP-1) is a Bax-associating protein highly enriched in the brain. In this study, we examined the role of MOAP-1 in promoting ischemic injuries following a stroke by investigating the consequences of MOAP-1 overexpression or deficiency in in vitro and in vivo models of ischemic stroke. MOAP-1 overexpressing SH-SY5Y cells showed significantly lower cell viability following oxygen and glucose deprivation (OGD) treatment when compared to control cells. Consistently, MOAP-1−/− primary cortical neurons were observed to be more resistant against OGD treatment than the MOAP-1+/+ primary neurons. In the mouse transient middle cerebral artery occlusion (tMCAO) model, ischemia triggered MOAP-1/Bax association, suggested activation of the MOAP-1-dependent apoptotic cascade. MOAP-1−/− mice were found to exhibit reduced neuronal loss and smaller infarct volume 24 h after tMCAO when compared to MOAP-1+/+ mice. Correspondingly, MOAP-1−/− mice also showed better integrity of neurological functions as demonstrated by their performance in the rotarod test. Therefore, both in vitro and in vivo data presented strongly support the conclusion that MOAP-1 is an important apoptotic modulator in ischemic injury. These results may suggest that a reduction of MOAP-1 function in the brain could be a potential therapeutic approach in the treatment of acute stroke.

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A Review on DNA Repair Inhibition by PARP Inhibitors in Cancer Therapy

Folia Medica ◽

10.1515/folmed-2017-0067 ◽

2018 ◽

Vol 60 (1) ◽

pp. 39-47 ◽

Cited By ~ 8

Author(s):

Ashish P. Shah ◽

Chhagan N. Patel ◽

Dipen K. Sureja ◽

Kirtan P. Sanghavi

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Cancer Therapy ◽

Repair Process ◽

Parp Inhibitors ◽

Brca Mutations ◽

Development Of Resistance ◽

Damage Repair ◽

Future Therapy

AbstractThe DNA repair process protects the cells from DNA damaging agent by multiple pathways. Majority of the cancer therapy cause DNA damage which leads to apoptosis. The cell has natural ability to repair this damage which ultimately leads to development of resistance of drugs. The key enzymes involved in DNA repair process are poly(ADP-ribose) (PAR) and poly(ADP-ribose) polymerases (PARP). Tumor cells repair their defective gene via defective homologues recombination (HR) in the presence of enzyme PARP. PARP inhibitors inhibit the enzyme poly(ADP-ribose) polymerases (PARPs) which lead to apoptosis of cancer cells. Current clinical data shows the role of PARP inhibitors is not restricted to BRCA mutations but also effective in HR dysfunctions related tumors. Therefore, investigation in this area could be very helpful for future therapy of cancer. This review gives detail information on the role of PARP in DNA damage repair, the role of PARP inhibitors and chemistry of currently available PARP inhibitors.

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SIRT7-mediated ATM deacetylation is essential for its deactivation and DNA damage repair

Science Advances ◽

10.1126/sciadv.aav1118 ◽

2019 ◽

Vol 5 (3) ◽

pp. eaav1118 ◽

Cited By ~ 19

Author(s):

Ming Tang ◽

Zhiming Li ◽

Chaohua Zhang ◽

Xiaopeng Lu ◽

Bo Tu ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Repair ◽

Class Iii ◽

Ataxia Telangiectasia Mutated ◽

Damage Repair ◽

Damage Response ◽

Late Stages

The activation of ataxia-telangiectasia mutated (ATM) upon DNA damage involves a cascade of reactions, including acetylation by TIP60 and autophosphorylation. However, how ATM is progressively deactivated after completing DNA damage repair remains obscure. Here, we report that sirtuin 7 (SIRT7)–mediated deacetylation is essential for dephosphorylation and deactivation of ATM. We show that SIRT7, a class III histone deacetylase, interacts with and deacetylates ATM in vitro and in vivo. In response to DNA damage, SIRT7 is mobilized onto chromatin and deacetylates ATM during the late stages of DNA damage response, when ATM is being gradually deactivated. Deacetylation of ATM by SIRT7 is prerequisite for its dephosphorylation by its phosphatase WIP1. Consequently, depletion of SIRT7 or acetylation-mimic mutation of ATM induces persistent ATM phosphorylation and activation, thus leading to impaired DNA damage repair. Together, our findings reveal a previously unidentified role of SIRT7 in regulating ATM activity and DNA damage repair.

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Regulation and pharmacological targeting of RAD51 in cancer

NAR Cancer ◽

10.1093/narcan/zcaa024 ◽

2020 ◽

Vol 2 (3) ◽

Author(s):

McKenzie K Grundy ◽

Ronald J Buckanovich ◽

Kara A Bernstein

Keyword(s):

Ovarian Cancer ◽

Dna Damage ◽

Homologous Recombination ◽

Patient Outcomes ◽

Cancer Biology ◽

Cancer Resistance ◽

Breast And Ovarian Cancer ◽

Resistance To Therapy ◽

Damage Repair

Abstract Regulation of homologous recombination (HR) is central for cancer prevention. However, too little HR can increase cancer incidence, whereas too much HR can drive cancer resistance to therapy. Importantly, therapeutics targeting HR deficiency have demonstrated a profound efficacy in the clinic improving patient outcomes, particularly for breast and ovarian cancer. RAD51 is central to DNA damage repair in the HR pathway. As such, understanding the function and regulation of RAD51 is essential for cancer biology. This review will focus on the role of RAD51 in cancer and beyond and how modulation of its function can be exploited as a cancer therapeutic.

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