RBMX involves in telomere stability maintenance by regulating TERRA expression

Telomeric repeat-containing RNA (TERRA) is a class of long noncoding RNAs (lncRNAs) that are transcribed from subtelomeric to telomeric region of chromosome ends. TERRA is prone to form R-loop structures at telomeres by invading into telomeric DNA. Excessive telomere R-loops result in telomere instability, so the TERRA level needs to be delicately modulated. However, the molecular mechanisms and factors controlling TERRA level are still largely unknown. In this study, we report that the RNA binding protein RBMX is a novel regulator of TERRA level and telomere integrity. The expression level of TERRA is significantly elevated in RBMX depleted cells, leading to enhanced telomere R-loop formation, replication stress, and telomere instability. We also found that RBMX binds to TERRA and the nuclear exosome targeting protein ZCCHC8 simultaneously, and that TERRA degradation slows down upon RBMX depletion, implying that RBMX promotes TERRA degradation by regulating its transportation to the nuclear exosome, which decays nuclear RNAs. Altogether, these findings uncover a new role of RBMX in TERRA expression regulation and telomere integrity maintenance, and raising RBMX as a potential target of cancer therapy. Telomeres are repetitive DNA: protein structures that protect linear chromosome ends from being recognized as double-strand DNA breaks. Telomeres bear very high loads of replication stress, and are essential for chromosomal stability and genome stability. Telomeric repeat-containing RNA (TERRA) is transcribed from subtelomeres to telomeres, and is prone to form R-loop structures by invading into telomeric DNA. In telomerase-negative human cancer cell lines, which maintain telomere length by homologous recombination-based alternative lengthening of telomeres (ALT) mechanism, both TERRA levels and telomeric R-loops are upregulated. Excessive telomere R-loops result in telomere instability. Therefore, only limited number of TERRA is required for telomere homeostasis. Here we show that, the RNA binding motif protein encoded on the X chromosome (RBMX), also known as hnRNP G, is a novel regulator of TERRA level and telomere integrity. Our data point to a completely new role of RBMX in TERRA expression regulation and telomere integrity maintenance, and open up a potential way for cancer therapy. In addition, this study also raises the possibility that RBMX also targeted other nuclear RNA to nuclear exosome for degradation.

Automated summary

Telomeric repeat-containing RNA (TERRA) is transcribed from subtelomeres to telomeres and prone to form R-loop structures at telomeres. This study reveals that the RNA binding protein RBMX is a novel regulator of TERRA level and telomere integrity. RBMX depletion results in elevated TERRA expression, enhanced telomere R-loop formation, replication stress, and telomere instability. RBMX promotes TERRA degradation by regulating its transportation to the nuclear exosome. These findings highlight the importance of RBMX in TERRA regulation and telomere maintenance, and suggest it as a potential target for cancer therapy.