气候变化领域集成服务门户(CCPortal): Cancer-specific loss of TERT activation sensitizes glioblastoma to DNA damage

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DOI	10.1073/pnas.2008772118
	Cancer-specific loss of TERT activation sensitizes glioblastoma to DNA damage
	Amen A.M.; Fellmann C.; Soczek K.M.; Ren S.M.; Lew R.J.; Knott G.J.; Park J.E.; McKinney A.M.; Mancini A.; Doudna J.A.; Costello J.F.
发表日期	2021
ISSN	00278424
卷号	118 期号:13
英文摘要	Most glioblastomas (GBMs) achieve cellular immortality by acquiring a mutation in the telomerase reverse transcriptase (TERT) promoter. TERT promoter mutations create a binding site for a GA binding protein (GABP) transcription factor complex, whose assembly at the promoter is associated with TERT reactivation and telomere maintenance. Here, we demonstrate increased binding of a specific GABPB1L-isoform–containing complex to the mutant TERT promoter. Furthermore, we find that TERT promoter mutant GBM cells, unlike wild-type cells, exhibit a critical near-term dependence on GABPB1L for proliferation, notably also posttumor establishment in vivo. Up-regulation of the protein paralogue GABPB2, which is normally expressed at very low levels, can rescue this dependence. More importantly, when combined with frontline temozolomide (TMZ) chemotherapy, inducible GABPB1L knockdown and the associated TERT reduction led to an impaired DNA damage response that resulted in profoundly reduced growth of intracranial GBM tumors. Together, these findings provide insights into the mechanism of cancer-specific TERT regulation, uncover rapid effects of GABPB1L-mediated TERT suppression in GBM maintenance, and establish GABPB1L inhibition in combination with chemotherapy as a therapeutic strategy for TERT promoter mutant GBM. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Cancer; CRISPR; Glioblastoma; Temozolomide; TERT
语种	英语
scopus关键词	GA binding protein; telomerase reverse transcriptase; temozolomide; Article; binding site; cancer survival; cell proliferation; controlled study; DNA damage; DNA damage response; down regulation; enzyme activation; enzyme mechanism; enzyme reactivation; glioblastoma; glioblastoma cell line; human; human cell; in vivo study; priority journal; tumor growth; U2OS cell line; upregulation
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180078
作者单位	Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, United States; Department of Neurological Surgery, University of California, San Francisco, CA 94158, United States; Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA 94158, United States; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, United States; Department of Chemistry, University of California, Berkeley, CA 94720, United States; Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, United States; HHMI, University of California, Berkeley, CA 94720, United States; Innovative Genomics Institute, University of California, Berkeley, CA 94720, United States
推荐引用方式 GB/T 7714	Amen A.M.,Fellmann C.,Soczek K.M.,et al. Cancer-specific loss of TERT activation sensitizes glioblastoma to DNA damage[J],2021,118(13).
APA	Amen A.M..,Fellmann C..,Soczek K.M..,Ren S.M..,Lew R.J..,...&Costello J.F..(2021).Cancer-specific loss of TERT activation sensitizes glioblastoma to DNA damage.Proceedings of the National Academy of Sciences of the United States of America,118(13).
MLA	Amen A.M.,et al."Cancer-specific loss of TERT activation sensitizes glioblastoma to DNA damage".Proceedings of the National Academy of Sciences of the United States of America 118.13(2021).