Regulation of Transcription Patterns, Poly(ADP-ribose), and RNA-DNA Hybrids by the ATM Protein Kinase

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2024 Mar 5

PMID 38442018

Authors

Phillip R Woolley

Xuemei Wen

Olivia M Conway

Nicolette A Ender

Ji-Hoon Lee

Tanya T Paull

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

A-T neurodegeneration and DNA damage-induced transcriptional stress.

Paull T, Woolley P DNA Repair (Amst). 2024; 135():103647.

PMID: 38377644 PMC: 11707827. DOI: 10.1016/j.dnarep.2024.103647.

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