scholarly journals DAXX-ATRX-H3.3 Regulation of p53 Chromatin Binding and DNA Damage Response

2021 ◽  
Author(s):  
Nitish Gulve ◽  
Zhong Deng ◽  
Samantha Soldan ◽  
Olga Vladimirova ◽  
Jayamanna Wickramasinghe ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Chromatin Binding ◽  
Rna Seq ◽  
Loss Of Function ◽  
Glioblastoma Cells ◽  
Histone H3.3 ◽  
Alternative Lengthening ◽  
Damage Response ◽  
Chaperone Complex

Abstract DAXX and ATRX are tumor suppressor proteins that form a histone H3.3 chaperone complex and are frequently mutated in cancers with the alternative lengthening of telomeres (ALT), such as pediatric glioblastoma. Rapid loss of function of either DAXX or ATRX are not by themselves sufficient to induce the ALT phenotype. However, cells lacking DAXX or ATRX can be readily selected for ALT-like features. Here, we show that DAXX and ATRX null glioblastoma cells with ALT-like features have defects in p53 chromatin binding and DNA damage response regulation. RNA-seq analysis of DAXX or ATRX null U87 glioblastoma cells with ALT-like features revealed that p53 pathway is among perturbed. ALT-selected DAXX and ATRX-null cells had aberrant response to DNA damaging agent etoposide. Both DAXX and ATRX-null ALT cells showed a loss of p53 binding at a subset of response elements. Complementation of DAXX null cells with a wild-type DAXX transgene rescued p53 binding and transcription, while the tumor associated mutation L130R that disrupts ATRX binding was incapable of rescuing p53 chromatin binding. We show that histone H3.3 binding is reduced in DAXX-null cells especially at subtelomeric p53 binding sites and telomere repeats. These findings indicate that DAXX and ATRX function to enable p53 chromatin binding through modulation of histone H3.3 binding, especially at sub-telomeric sites.

scholarly journals Profilin-1; a novel regulator of DNA damage response and repair machinery in keratinocytes

2021 ◽  
Author(s):  
Chang-Jin Lee ◽  
Min-Ji Yoon ◽  
Dong Hyun Kim ◽  
Tae Uk Kim ◽  
Youn-Jung Kang
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Response ◽  
Recovery Time ◽  
Actin Polymerization ◽  
Loss Of Function ◽  
Dna Double Strand Breaks ◽  
Pten Loss ◽  
Damage Response ◽  
Specific Regulation

AbstractProfilin-1 (PFN1) regulates actin polymerization and cytoskeletal growth. Despite the essential roles of PFN1 in cell integration, its subcellular function in keratinocyte has not been elucidated yet. Here we characterize the specific regulation of PFN1 in DNA damage response and repair machinery. PFN1 depletion accelerated DNA damage-mediated apoptosis exhibiting PTEN loss of function instigated by increased phosphorylated inactivation followed by high levels of AKT activation. PFN1 changed its predominant cytoplasmic localization to the nucleus upon DNA damage and subsequently restored the cytoplasmic compartment during the recovery time. Even though γH2AX was recruited at the sites of DNA double strand breaks in response to DNA damage, PFN1-deficient cells failed to recruit DNA repair factors, whereas control cells exhibited significant increases of these genes. Additionally, PFN1 depletion resulted in disruption of PTEN-AKT cascade upon DNA damage and CHK1-mediated cell cycle arrest was not recovered even after the recovery time exhibiting γH2AX accumulation. This might suggest PFN1 roles in regulating DNA damage response and repair machinery to protect cells from DNA damage. Future studies addressing the crosstalk and regulation of PTEN-related DNA damage sensing and repair pathway choice by PFN1 may further aid to identify new mechanistic insights for various DNA repair disorders.

scholarly journals PIMREG expression level predicts glioblastoma patient survival and affects temozolomide resistance and DNA damage response

2021 ◽  
Author(s):  
Rodolfo Bortolozo Serafim ◽  
Cibele Cardoso ◽  
Vanessa Arfelli ◽  
Valeria Valente ◽  
Leticia Fröhlich Archangelo
Keyword(s):  
Dna Damage ◽  
Nervous System ◽  
Dna Damage Response ◽  
Cellular Proliferation ◽  
Patient Survival ◽  
Glioblastoma Cells ◽  
Damage Response ◽  
Genotoxic Agents ◽  
And Migration ◽  
And Function

Abstract PIMREG expression strongly correlates with cellular proliferation in both malignant and normal cells. Throughout embryo development, PIMREG expression is prominent at the central nervous system. Recent studies have described high levels of PIMREG transcripts in different types of tumors and correlated with patient survival and tumor aggressiveness. Given the emerging significance of PIMREG in carcinogenesis and its putative role in the context of the nervous system, we investigated the expression and function of PIMREG in gliomas, the most common primary brain tumors. We performed an extensive analysis of PIMREG expression in tumors samples of glioma patients, assessed the effects of PIMREG silencing and overexpression on the sensitivity of glioblastoma cell lines treated with genotoxic agents commonly used for treating patients and assessed for treatment response, proliferation and migration. We show that glioblastoma exhibits the highest levels of PIMREG expression among all cancers analyzed and that elevated PIMREG expression is a biomarker for glioma progression and patient outcome. Moreover, PIMREG is induced by genotoxic agents and its silencing renders glioblastoma cells sensitive to temozolomide treatment and affects ATR- and ATM-dependent signaling. Our data demonstrate that PIMREG plays a role in DNA damage response and temozolomide resistance of glioblastoma cells and further support the PIMREG role in tumorigenesis.

MiR-338-5p sensitizes glioblastoma cells to radiation through regulation of genes involved in DNA damage response

Tumor Biology ◽  
2015 ◽  
Vol 37 (6) ◽  
pp. 7719-7727 ◽  
Author(s):  
Andrej Besse ◽  
Jiri Sana ◽  
Radek Lakomy ◽  
Leos Kren ◽  
Pavel Fadrus ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Glioblastoma Cells ◽  
Damage Response

DNA damage response and anti-apoptotic proteins predict radiosensitization efficacy of HDAC inhibitors SAHA and LBH589 in patient-derived glioblastoma cells

2015 ◽  
Vol 356 (2) ◽  
pp. 525-535 ◽  
Author(s):  
Lotte M.E. Berghauser Pont ◽  
Kishan Naipal ◽  
Jenneke J. Kloezeman ◽  
Subramanian Venkatesan ◽  
Martin van den Bent ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Hdac Inhibitors ◽  
Glioblastoma Cells ◽  
Damage Response ◽  
Apoptotic Proteins

scholarly journals Regulation of Rtt107 Recruitment to Stalled DNA Replication Forks by the Cullin Rtt101 and the Rtt109 Acetyltransferase

2008 ◽  
Vol 19 (1) ◽  
pp. 171-180 ◽  
Author(s):  
Tania M. Roberts ◽  
Iram Waris Zaidi ◽  
Jessica A. Vaisica ◽  
Matthias Peter ◽  
Grant W. Brown
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Replication Forks ◽  
Chromatin Binding ◽  
Direct Role ◽  
Repair Enzymes ◽  
Damage Response ◽  
Stalled Replication Forks

RTT107 (ESC4, YHR154W) encodes a BRCA1 C-terminal domain protein that is important for recovery from DNA damage during S phase. Rtt107 is a substrate of the checkpoint kinase Mec1, and it forms complexes with DNA repair enzymes, including the nuclease subunit Slx4, but the role of Rtt107 in the DNA damage response remains unclear. We find that Rtt107 interacts with chromatin when cells are treated with compounds that cause replication forks to arrest. This damage-dependent chromatin binding requires the acetyltransferase Rtt109, but it does not require acetylation of the known Rtt109 target, histone H3-K56. Chromatin binding of Rtt107 also requires the cullin Rtt101, which seems to play a direct role in Rtt107 recruitment, because the two proteins are found in complex with each other. Finally, we provide evidence that Rtt107 is bound at or near stalled replication forks in vivo. Together, these results indicate that Rtt109, Rtt101, and Rtt107, which genetic evidence suggests are functionally related, form a DNA damage response pathway that recruits Rtt107 complexes to damaged or stalled replication forks.

scholarly journals Decoupling of DNA damage response signaling from DNA damages underlies temozolomide resistance in glioblastoma cells

2010 ◽  
Vol 24 (6) ◽  
pp. 424-435 ◽  
Author(s):  
Bo Cui ◽  
Stewart P. Johnson ◽  
Nancy Bullock ◽  
Francis Ali-Osman ◽  
Darell D. Bigner ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Glioblastoma Cells ◽  
Dna Damages ◽  
Damage Response

scholarly journals VRK1 Depletion Facilitates the Synthetic Lethality of Temozolomide and Olaparib in Glioblastoma Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Elena Navarro-Carrasco ◽  
Pedro A. Lazo
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Tumor Cell ◽  
Dna Damage Response ◽  
Synthetic Lethality ◽  
Glioblastoma Cell ◽  
Glioblastoma Cells ◽  
Tumor Cell Death ◽  
Damage Response ◽  
Parp 1

BackgroundGlioblastomas treated with temozolomide frequently develop resistance to pharmacological treatments. Therefore, there is a need to find alternative drug targets to reduce treatment resistance based on tumor dependencies. A possibility is to target simultaneously two proteins from different DNA-damage repair pathways to facilitate tumor cell death. Therefore, we tested whether targeting the human chromatin kinase VRK1 by RNA interference can identify this protein as a novel molecular target to reduce the dependence on temozolomide in combination with olaparib, based on synthetic lethality.Materials and MethodsDepletion of VRK1, an enzyme that regulates chromatin dynamic reorganization and facilitates resistance to DNA damage, was performed in glioblastoma cells treated with temozolomide, an alkylating agent used for GBM treatment; and olaparib, an inhibitor of PARP-1, used as sensitizer. Two genetically different human glioblastoma cell lines, LN-18 and LN-229, were used for these experiments. The effect on the DNA-damage response was followed by determination of sequential steps in this process: H4K16ac, γH2AX, H4K20me2, and 53BP1.ResultsThe combination of temozolomide and olaparib increased DNA damage detected by labeling free DNA ends, and chromatin relaxation detected by H4K16ac. The combination of both drugs, at lower doses, resulted in an increase in the DNA damage response detected by the formation of γH2AX and 53BP1 foci. VRK1 depletion did not prevent the generation of DNA damage in TUNEL assays, but significantly impaired the DNA damage response induced by temozolomide and olaparib, and mediated by γH2AX, H4K20me2, and 53BP1. The combination of these drugs in VRK1 depleted cells resulted in an increase of glioblastoma cell death detected by annexin V and the processing of PARP-1 and caspase-3.ConclusionDepletion of the chromatin kinase VRK1 promotes tumor cell death at lower doses of a combination of temozolomide and olaparib treatments, and can be a novel alternative target for therapies based on synthetic lethality.

DNA damage response of clinical carbon ion versus photon radiation in human glioblastoma cells

2019 ◽  
Vol 133 ◽  
pp. 77-86 ◽  
Author(s):  
Ramon Lopez Perez ◽  
Nils H. Nicolay ◽  
Jörg-Christian Wolf ◽  
Moritz Frister ◽  
Peter Schmezer ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Photon Radiation ◽  
Glioblastoma Cells ◽  
Human Glioblastoma ◽  
Carbon Ion ◽  
Damage Response ◽  
Human Glioblastoma Cells

Exploring impact of mutations in non-BRCA DNA damage response (DDR) and non-DDR genes on efficacy in phase III EMBRACA study of talazoparib (TALA) in patients (pts) with germline BRCA1/2 mutated (gBRCAm) HER2-negative (HER2-) advanced breast cancer (ABC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1018-1018
Author(s):  
Jennifer Keating Litton ◽  
Douglas Laird ◽  
Hope S. Rugo ◽  
Johannes Ettl ◽  
Sara A. Hurvitz ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Tumor Response ◽  
Brca Mutation ◽  
Phase Iii ◽  
Loss Of Function ◽  
Single Nucleotide Variants ◽  
Tp53 Mutations ◽  
Mutational Status ◽  
Damage Response

1018 Background: Loss-of-function mutations in genes encoding components of the homologous recombination DNA damage response (DDR) machinery, notably BRCA1/2, are associated with tumor sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi). In EMBRACA, the PARPi TALA showed an improvement in progression-free survival (PFS) (HR [95% CI] 0.54 [0.41-0.71], P < 0.001) vs physician's choice of chemotherapy (PCT) in g BRCAm HER2− ABC. Methods: Baseline tumor tissue from 308 pts (71%; intent-to-treat) was sequenced using the FoundationOne CDx panel. Mutations summarized below were known/likely pathogenic single-nucleotide variants, insertions, deletions, or rearrangements. Best tumor response (BOR) was using RECIST 1.1 by Investigator (confirmation of CR or PR not required). Results: 296/308 (96%) of evaluable pts exhibited ≥1 tumor BRCA mutation, with 7 of the remaining 12 exhibiting BRCA copy number alterations deemed pathogenic. Mutations in other genes implicated in DDR and/or potential sensitization to PARPi were rare, with mutations detected in BARD1, CDK12, FANCG, STAG2 (each 0.3%), ATR, BRD4, FANCC, PALB2, RAD51B (0.6%), ATM, BRIP1 (1.0%), NBN (1.3%), CHEK2, FANCA (1.6%), and ARID1A (2.3%). No association was observed between total number of DDR mutations, including BRCA1/2, and best tumor response (BOR) [odds ratio of 1 vs ≥2 DDR mutations (95% CI): TALA, 0.76 (0.31-1.87), P = 0.55; PCT, 0.98 (0.27-3.51), P = 0.97]. TP53 and PIK3CA were the most commonly mutated non- BRCA genes in BRCAm tumors (52.0 and 10.8%, respectively). TP53 mutations were more prevalent in BRCA1m vs BRCA2m tumors (85.2 vs 24.8%). PIK3CA mutations were more prevalent in BRCA2m vs BRCA1m tumors (15.9 vs 5.2%). With TALA, PFS was significantly shorter in pts with TP53 mutations than without [HR (95% CI) 1.693 (1.186-2.418), P = 0.0033]. A similar, non-significant, trend was evident with PCT [HR (95% CI) 1.439 (0.859-2.411), P = 0.1614]. PIK3CA mutational status had no impact on PFS in either arm. Conclusions: Selection based on g BRCA mutational status is appropriate to identify HER2─ ABC pts with potential for clinical benefit from TALA, with the total number of tumor mutations in BRCA1/2 and other DDR genes not impacting response (within the g BRCAm subset). TP53 mutations were associated with shorter PFS, likely reflecting the worse outcomes observed in g BRCA1m patients. Additional correlative analyses are ongoing. Clinical trial information: NCT01945775 .

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