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Long interspersed element-1 ribonucleoprotein particles protect telomeric ends in alternative lengthening of telomeres dependent cells.
- Source :
-
Neoplasia (New York, N.Y.) [Neoplasia] 2020 Feb; Vol. 22 (2), pp. 61-75. Date of Electronic Publication: 2019 Dec 14. - Publication Year :
- 2020
-
Abstract
- Malignant cells ensure telomere maintenance by the alternative lengthening of telomeres (ALT) in the absence of telomerase activity (TA). The retrotransposons "long interspersed nuclear element-1" (LINE-1, L1) are expressed in malignant cells and are primarily known to contribute to complex karyotypes. Here we demonstrate that LINE-1 ribonucleoprotein particles (L1-RNPs) expression is significantly higher in ALT <superscript>+</superscript> - versus in TA <superscript>+</superscript> -human glioma. Analyzing a role of L1-RNP in ALT, we show that L1-RNPs bind to telomeric repeat containing RNA (TERRA), which is critical for telomere stabilization and which is overexpressed in ALT <superscript>+</superscript> cells. In turn, L1-RNP knockdown (KD) abrogated the nuclear retention of TERRA, resulted in increased telomeric DNA damage, decreased cell growth and reduced expression of ALT characteristics such as c-circles and PML-bodies. L1-RNP KD also decreased the expression of Shelterin- and the ALT-regulating protein Topoisomerase IIIα (TopoIIIα) indicating a more general role of L1-RNPs in supporting telomeric integrity in ALT. Our findings suggest an impact of L1-RNP on telomere stability in ALT <superscript>+</superscript> dependent tumor cells. As L1-RNPs are rarely expressed in normal adult human tissue those elements might serve as a novel target for tumor ablative therapy.<br /> (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Cell Line, Tumor
DNA Damage genetics
Glioma pathology
Humans
Long Interspersed Nucleotide Elements genetics
Ribonucleoproteins genetics
Telomere Homeostasis genetics
DNA Topoisomerases, Type I genetics
DNA-Binding Proteins genetics
Glioma genetics
Telomere genetics
Transcription Factors genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5586
- Volume :
- 22
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Neoplasia (New York, N.Y.)
- Publication Type :
- Academic Journal
- Accession number :
- 31846834
- Full Text :
- https://doi.org/10.1016/j.neo.2019.11.002