Long noncoding RNA BS-DRL1 modulates the DNA damage response and genome stability by interacting with HMGB1 in neurons

Min-Min Lou ,Guangming Wang ,Jian Wang ,Huan Zou ,Libing Shen ,Junying Wang ,Fang Luo ,Liu‐Lin Xiong ,Jun Xu ,Guoming Ma ,Yi Wu ,Aibin Liang ,Qili Shi ,Yaoyang Zhang ,Ting‐Hua Wang ,Jia He ,Mingzhi Guan ,Qun Zhang ,Fei Wang ,Xiaoqiang Tang ,Ming-Jian Xu ,Wenyuan Wang

doi:10.1038/s41467-021-24236-z

Abstract

Long noncoding RNAs (lncRNAs) are known to regulate DNA damage response (DDR) and genome stability in proliferative cells. However, it remains unknown whether lncRNAs are involved in these vital biological processes in post-mitotic neurons. Here, we report and characterize a lncRNA, termed Brain Specific DNA-damage Related lncRNA1 (BS-DRL1), in the central nervous system. BS-DRL1 is a brain-specific lncRNA and depletion of BS-DRL1 in neurons leads to impaired DDR upon etoposide treatment in vitro. Mechanistically, BS-DRL1 interacts with HMGB1, a chromatin protein that is important for genome stability, and is essential for the assembly of HMGB1 on chromatin. BS-DRL1 mediated DDR exhibits cell-type specificity in the cortex and cerebellum in gamma-irradiated mice and BS-DRL1 knockout mice show impaired motor function and concomitant purkinje cell degeneration. Our study extends the understanding of lncRNAs in DDR and genome stability and implies a protective role of lncRNA against neurodegeneration.

Highlights

Long noncoding RNAs are known to regulate DNA damage response (DDR) and genome stability in proliferative cells
In an initial screen to identify Long noncoding RNAs (lncRNAs) involved in DDR, we found that neurons expressing shRNAs against Mir9-3hg exhibited altered DDR (Supplementary Fig. 1b, c and Fig. 1g), so we focused on this lncRNA in our study
When analyzing our RNA-Seq data with primary neurons, we unexpectedly found that in addition to the 4 annotated transcripts, there were 5 new transcripts of Brain Specific DNA-damage Related lncRNA1 (BS-DRL1), three of which are highly expressed in the brain (Fig. 1b)

Summary

Introduction

Long noncoding RNAs (lncRNAs) are known to regulate DNA damage response (DDR) and genome stability in proliferative cells. LncRNAs are arbitrarily defined as a group of transcripts longer than 200 nucleotides that are generally not translated into proteins, but are functionally involved in many physiological and pathological processes, including development, aging, and diseases through modulating the activity of associated proteins or mRNAs, organizing subnuclear structure, and mediating chromosomal interactions[1,2,3] Due to their general low abundance and modest evolutionary conservation compared to protein-coding genes, the biological roles and the related molecular mechanisms for the majority of lncRNAs remain unexplored[4]. The DNA damage and genome instability incurred by either endogenous cellular metabolic products, such as 8-oxo-dG, or environmental chemicals can lead to the accumulation of unrepaired or erroneously-repaired DNA breaks, and the alteration of chromatin organization Together, these destructive changes can profoundly affect the integrity of neuronal functions and contribute to brain aging and to neurodegeneration[8].

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Results

Conclusion