Regulation of transcription patterns, poly(ADP-ribose), and RNA-DNA hybrids by the ATM protein kinase.

Autor:	Woolley PR; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA., Wen X; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA., Conway OM; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA., Ender NA; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA., Lee JH; Department of Biological Sciences, Research Center of Ecomimetics, Chonnam National University, Gwangju 61186, Republic of Korea. Electronic address: microljh@jnu.ac.kr., Paull TT; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA. Electronic address: tpaull@utexas.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2024 Mar 26; Vol. 43 (3), pp. 113896. Date of Electronic Publication: 2024 Mar 04.
DOI:	10.1016/j.celrep.2024.113896
Abstrakt:	The ataxia telangiectasia mutated (ATM) protein kinase is a master regulator of the DNA damage response and also an important sensor of oxidative stress. Analysis of gene expression in ataxia-telangiectasia (A-T) patient brain tissue shows that large-scale transcriptional changes occur in patient cerebellum that correlate with the expression level and guanine-cytosine (GC) content of transcribed genes. In human neuron-like cells in culture, we map locations of poly(ADP-ribose) and RNA-DNA hybrid accumulation genome-wide with ATM inhibition and find that these marks also coincide with high transcription levels, active transcription histone marks, and high GC content. Antioxidant treatment reverses the accumulation of R-loops in transcribed regions, consistent with the central role of reactive oxygen species in promoting these lesions. Based on these results, we postulate that transcription-associated lesions accumulate in ATM-deficient cells and that the single-strand breaks and PARylation at these sites ultimately generate changes in transcription that compromise cerebellum function and lead to neurodegeneration over time in A-T patients. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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