Identification of ATM-dependent long non-coding RNAs induced in response to DNA damage

Area of Science:

• Molecular Biology
• Genetics
• Cell Biology

Background:

• DNA double-strand breaks (DSBs) are critical DNA damage events.
• The ATM kinase is central to DNA damage response (DDR).
• Long non-coding RNAs (lncRNAs) are increasingly recognized for their roles in cellular processes.

Purpose of the Study:

• To identify lncRNAs induced by DNA damage in an ATM-dependent manner.
• To investigate the role of lncRNAs in the cellular response to DNA damage.

Main Methods:

• Ionizing radiation (IR) was used to induce DNA damage in lymphoblastoid cell lines from healthy donors and ataxia-telangiectasia (AT) patients.
• RNA sequencing (RNA-seq) was performed to analyze lncRNA and mRNA expression.
• Quantitative real-time PCR (RT-qPCR) validated lncRNA induction.
• ATM inhibition and subcellular fractionation were used to further characterize lncRNA function and localization.

Main Results:

• 10 and 149 lncRNAs were significantly induced by IR in healthy donors at 1h and 8h, respectively, with minimal induction in AT patients.
• ATM kinase activity is crucial for the induction of these IR-responsive lncRNAs.
• Gene expression analysis revealed delayed DDR pathway activation in AT patients.
• Many identified lncRNAs are located near DDR-related genes and their induction precedes changes in adjacent gene expression.
• The majority of the studied lncRNAs were found to be chromatin-localized.

Conclusions:

• Several lncRNAs are induced by ionizing radiation in an ATM-dependent manner.
• These lncRNAs may function as regulators of nearby genes involved in DNA damage response.
• The findings highlight a novel role for lncRNAs in the complex DNA damage response network.