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

被引：2

作者：

Podralska, Marta ^{[1
]}

Sajek, Marcin Piotr ^{[1
,2
,3
]}

Bielicka, Antonina ^{[1
]}

Zurawek, Magdalena ^{[1
]}

Ziolkowska-Suchanek, Iwona ^{[1
]}

Izykowska, Katarzyna ^{[1
]}

Kolenda, Tomasz ^{[4
]}

Kazimierska, Marta ^{[1
]}

Kasprzyk, Marta Elzbieta ^{[1
]}

Sura, Weronika ^{[1
]}

Pietrucha, Barbara ^{[1
,5
]}

Cukrowska, Bozena ^{[6
]}

Rozwadowska, Natalia ^{[1
]}

Dzikiewicz-Krawczyk, Agnieszka ^{[1
,7
]}

机构：

[1] Polish Acad Sci, Inst Human Genet, Poznan, Poland

[2] Univ Colorado, Sch Med, RNA Biosci Initiat, Aurora, CO 80045 USA

[3] Univ Colorado, Sch Med, Dept Biochem & Mol Genet, Aurora, CO 80045 USA

[4] Greater Poland Canc Ctr, Lab Canc Genet, Poznan, Poland

[5] Childrens Mem Hlth Inst, Dept Immunol, Warsaw, Poland

[6] Childrens Mem Hlth Inst, Dept Pathomorphol, Immunol Lab, Warsaw, Poland

[7] Strzeszynska 32, PL-60479 Poznan, Poland

来源：

DNA REPAIR | 2024年 / 135卷

关键词：

ATM; Ataxia-telangiectasia; Long non-coding RNA; DNA damage; Ionizing radiation;

D O I：

10.1016/j.dnarep.2024.103648

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

DNA damage response (DDR) is a complex process, essential for cell survival. Especially deleterious type of DNA damage are DNA double-strand breaks (DSB), which can lead to genomic instability and malignant transformation if not repaired correctly. The central player in DSB detection and repair is the ATM kinase which orchestrates the action of several downstream factors. Recent studies have suggested that long non-coding RNAs (lncRNAs) are involved in DDR. Here, we aimed to identify lncRNAs induced upon DNA damage in an ATMdependent manner. DNA damage was induced by ionizing radiation (IR) in immortalized lymphoblastoid cell lines derived from 4 patients with ataxia-telangiectasia (AT) and 4 healthy donors. RNA-seq revealed 10 lncRNAs significantly induced 1 h after IR in healthy donors, whereas none in AT patients. 149 lncRNAs were induced 8 h after IR in the control group, while only three in AT patients. Among IR-induced mRNAs, we found several genes with well-known functions in DDR. Gene Set Enrichment Analysis and Gene Ontology revealed delayed induction of key DDR pathways in AT patients compared to controls. The induction and dynamics of selected 9 lncRNAs were confirmed by RT-qPCR. Moreover, using a specific ATM inhibitor we proved that the induction of those lncRNAs is dependent on ATM. Some of the detected lncRNA genes are localized next to protein-coding genes involved in DDR. We observed that induction of lncRNAs after IR preceded changes in expression of adjacent genes. This indicates that IR-induced lncRNAs may regulate the transcription of nearby genes. Subcellular fractionation into chromatin, nuclear, and cytoplasmic fractions revealed that the majority of studied lncRNAs are localized in chromatin. In summary, our study revealed several lncRNAs induced by IR in an ATM-dependent manner. Their genomic co-localization and co-expression with genes involved in DDR suggest that those lncRNAs may be important players in cellular response to DNA damage.

引用

页数：9