The Lingner lab investigated the roles THO Complex's function in telomere homeostasis, and found that it hinders TERRA association with telomeres, lowers telomere fragility and recombination. Their findings have been published in the article "The THO complex counteracts TERRA R-loop-mediated telomere fragility in telomerase+ cells and telomeric recombination in ALT+ cells" in Nucleic Acids Research.
Abstract
Telomeres are the nucleoprotein structures at the ends of linear chromosomes. Telomeres are transcribed into long non-coding Telomeric Repeat-Containing RNA (TERRA), whose functions rely on its ability to associate with telomeric chromatin. The conserved THO complex (THOC) was previously identified at human telomeres. It links transcription with RNA processing, decreasing the accumulation of co-transcriptional DNA:RNA hybrids throughout the genome. Here, we explore the role of THOC at human telomeres, as a regulator of TERRA localization to chromosome ends. We show that THOC counteracts TERRA association with telomeres via R-loops formed co-transcriptionally and also post-transcriptionally, in trans. We demonstrate that THOC binds nucleoplasmic TERRA, and that RNaseH1 loss, which increases telomeric R-loops, promotes THOC occupancy at telomeres. Additionally, we show that THOC counteracts lagging and mainly leading strand telomere fragility, suggesting that TERRA R-loops can interfere with replication fork progression. Finally, we observed that THOC suppresses telomeric sister-chromatid exchange and C-circle accumulation in ALT cancer cells, which maintain telomeres by recombination. Altogether, our findings reveal crucial roles of THOC in telomeric homeostasis through the co- and post-transcriptional regulation of TERRA R-loops.
Read the Publication in Nucleic Acids Research (Open Access)
Abstract and figure from Valador Fernandes and Lingner Nucleic Acids Res (2023) published under a CC BY 4.0 license.