| Literature DB >> 35021084 |
Tingting Qin1, Brendan Mullan2, Ramya Ravindran2, Dana Messinger2, Ruby Siada2, Jessica R Cummings2, Micah Harris2, Ashwath Muruganand2, Kalyani Pyaram3, Zachary Miklja2, Mary Reiber2, Taylor Garcia2, Dustin Tran2, Carla Danussi4, Jacqueline Brosnan-Cashman5, Drew Pratt6, Xinyi Zhao7, Alnawaz Rehemtulla7, Maureen A Sartor8, Sriram Venneti6, Alan K Meeker5, Jason T Huse4, Meredith A Morgan7, Pedro R Lowenstein9, Maria G Castro9, Viveka Nand Yadav2, Carl Koschmann10.
Abstract
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.Entities:
Keywords: ATM inhibitor; ATRX; CHEK1; cell-cycle; epigenetics; glioma
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Year: 2022 PMID： 35021084 PMCID： PMC8759735 DOI： 10.1016/j.celrep.2021.110216
Source DB: PubMed Journal: Cell Rep Impact factor: 9.995