Find in Library
Search millions of books, articles, and more
Indexed Open Access Databases
Long interspersed element-1 ribonucleoprotein particles protect telomeric ends in alternative lengthening of telomeres dependent cells
oleh: Thomas Aschacher, Brigitte Wolf, Olivia Aschacher, Florian Enzmann, Viktoria Laszlo, Barbara Messner, Adrian Türkcan, Serge Weis, Sabine Spiegl-Kreinecker, Klaus Holzmann, Günther Laufer, Marek Ehrlich, Michael Bergmann
Format: | Article |
---|---|
Diterbitkan: | Elsevier 2020-02-01 |
Deskripsi
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+- versus in TA+-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+ 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+ 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. Keywords: Telomere, TERRA, LINE-1, DNA damage response, Alternative lengthening of telomeres