ATRX loss in glioma results in dysregulation of cell-cycle phase transition and ATM inhibitor radio-sensitization.

Animals Brain Neoplasms / metabolism Cell Cycle / genetics Cell Cycle Checkpoints / genetics Cell Line, Tumor Checkpoint Kinase 1 / metabolism Female Glioma / metabolism Histones / metabolism Humans Isocitrate Dehydrogenase / genetics Male Mice Mice, Inbred C57BL Mutation Neoplasm Recurrence, Local / metabolism Primary Cell Culture X-linked Nuclear Protein / genetics
ATM inhibitor ATRX CHEK1 cell-cycle epigenetics glioma

Journal

Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691

Informations de publication

Date de publication:
11 01 2022
Historique:
received: 11 06 2021
revised: 15 10 2021
accepted: 15 12 2021
entrez: 12 1 2022
pubmed: 13 1 2022
medline: 15 2 2022
Statut: ppublish

Résumé

ATRX, a chromatin remodeler protein, is recurrently mutated in H3F3A-mutant pediatric glioblastoma (GBM) and isocitrate dehydrogenase (IDH)-mutant grade 2/3 adult glioma. Previous work has shown that ATRX-deficient GBM cells show enhanced sensitivity to irradiation, but the etiology remains unclear. We find that ATRX binds the regulatory elements of cell-cycle phase transition genes in GBM cells, and there is a marked reduction in Checkpoint Kinase 1 (CHEK1) expression with ATRX loss, leading to the early release of G2/M entry after irradiation. ATRX-deficient cells exhibit enhanced activation of master cell-cycle regulator ATM with irradiation. Addition of the ATM inhibitor AZD0156 doubles median survival in mice intracranially implanted with ATRX-deficient GBM cells, which is not seen in ATRX-wild-type controls. This study demonstrates that ATRX-deficient high-grade gliomas (HGGs) display Chk1-mediated dysregulation of cell-cycle phase transitions, which opens a window for therapies targeting this phenotype.

Identifiants

DOI: 10.1016/j.celrep.2021.110216 PMID: 35021084 PMC: PMC8759735
pubmed: 35021084
pii: S2211-1247(21)01720-4
doi: 10.1016/j.celrep.2021.110216
pmc: PMC8759735
mid: NIHMS1767352
pii:
doi:

Substances chimiques

Histones 0
Isocitrate Dehydrogenase EC 1.1.1.41
CHEK1 protein, human EC 2.7.11.1
Checkpoint Kinase 1 EC 2.7.11.1
Chek1 protein, mouse EC 2.7.11.1
ATRX protein, human EC 3.6.4.12
Atrx protein, mouse EC 3.6.4.12
X-linked Nuclear Protein EC 3.6.4.12

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

110216

Subventions

Organisme : NINDS NIH HHS
ID : R01 NS122165
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS105556
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA216449
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS082311
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA046592
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS110572
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA240515
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009676
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES017885
Pays : United States
Organisme : NINDS NIH HHS
ID : R37 NS094804
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS122234
Pays : United States
Organisme : NINDS NIH HHS
ID : K08 NS099427
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS107894
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS119231
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS096756
Pays : United States

Informations de copyright

Copyright © 2021. Published by Elsevier Inc.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.

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Auteurs

Tingting Qin (T)

Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Rogel Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Brendan Mullan (B)

Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Michigan Medical School, 3520D MSRB 1, 1150 W Medical Center Drive, Ann Arbor, MI 48109, USA.

Ramya Ravindran (R)

Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Michigan Medical School, 3520D MSRB 1, 1150 W Medical Center Drive, Ann Arbor, MI 48109, USA.

Dana Messinger (D)

Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Michigan Medical School, 3520D MSRB 1, 1150 W Medical Center Drive, Ann Arbor, MI 48109, USA.

Ruby Siada (R)

Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Michigan Medical School, 3520D MSRB 1, 1150 W Medical Center Drive, Ann Arbor, MI 48109, USA.

Jessica R Cummings (JR)

Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Michigan Medical School, 3520D MSRB 1, 1150 W Medical Center Drive, Ann Arbor, MI 48109, USA.

Micah Harris (M)

Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Michigan Medical School, 3520D MSRB 1, 1150 W Medical Center Drive, Ann Arbor, MI 48109, USA.

Ashwath Muruganand (A)

Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Michigan Medical School, 3520D MSRB 1, 1150 W Medical Center Drive, Ann Arbor, MI 48109, USA.

Kalyani Pyaram (K)

Division of Biology, Kansas State University, Manhattan, KS 66506, USA.

Zachary Miklja (Z)

Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Michigan Medical School, 3520D MSRB 1, 1150 W Medical Center Drive, Ann Arbor, MI 48109, USA.

Mary Reiber (M)

Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Michigan Medical School, 3520D MSRB 1, 1150 W Medical Center Drive, Ann Arbor, MI 48109, USA.

Taylor Garcia (T)

Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Michigan Medical School, 3520D MSRB 1, 1150 W Medical Center Drive, Ann Arbor, MI 48109, USA.

Dustin Tran (D)

Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Michigan Medical School, 3520D MSRB 1, 1150 W Medical Center Drive, Ann Arbor, MI 48109, USA.

Carla Danussi (C)

Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Jacqueline Brosnan-Cashman (J)

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Drew Pratt (D)

Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Xinyi Zhao (X)

Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Alnawaz Rehemtulla (A)

Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Maureen A Sartor (MA)

Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Sriram Venneti (S)

Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Alan K Meeker (AK)

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Jason T Huse (JT)

Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Meredith A Morgan (MA)

Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Pedro R Lowenstein (PR)

Departments of Neurosurgery and Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Maria G Castro (MG)

Departments of Neurosurgery and Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Viveka Nand Yadav (VN)

Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Michigan Medical School, 3520D MSRB 1, 1150 W Medical Center Drive, Ann Arbor, MI 48109, USA.

Carl Koschmann (C)

Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Michigan Medical School, 3520D MSRB 1, 1150 W Medical Center Drive, Ann Arbor, MI 48109, USA. Electronic address: ckoschma@med.umich.edu.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › ATRX loss in glioma results in dysregulation...
questionsmedicales.fr › Maladies du système nerveux › Tumeurs du système nerveux › Tumeurs du système nerveux central › Tumeurs du cerveau › ATRX loss in glioma results in dysregulation...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Cycle cellulaire › ATRX loss in glioma results in dysregulation...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Cycle cellulaire › Points de contrôle du cycle cellulaire › ATRX loss in glioma results in dysregulation...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › ATRX loss in glioma results in dysregulation...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Checkpoint kinase 1 › ATRX loss in glioma results in dysregulation...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs du tissu nerveux › Tumeurs neuroectodermiques › Tumeurs neuroépitheliales › Gliome › ATRX loss in glioma results in dysregulation...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Histone › ATRX loss in glioma results in dysregulation...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › ATRX loss in glioma results in dysregulation...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Oxidoreductases › Alcohol oxidoreductases › NAD (+) and NADP (+) dependent Alcohol oxidoreductases › Isocitrate dehydrogenases › ATRX loss in glioma results in dysregulation...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › ATRX loss in glioma results in dysregulation...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › ATRX loss in glioma results in dysregulation...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › ATRX loss in glioma results in dysregulation...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Récidive tumorale locale › ATRX loss in glioma results in dysregulation...
questionsmedicales.fr › Techniques d'investigation › Techniques in vitro › Techniques de culture › Techniques de culture cellulaire › Culture de cellules primaires › ATRX loss in glioma results in dysregulation...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Isomerases › Helicase › Protéine nucléaire liée à l'X › ATRX loss in glioma results in dysregulation...