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.

Serum lipoprotein and RBC rigidity index to predict cerebral infarction in patients with carotid artery stenosis.

OBJECTIVE: This study aims to determine the risk factors and to predict the occurrence of cerebral infarction in patients with carotid artery stenosis. METHODS: Two hundred and one subjects with carotid artery stenosis were retrospectively selected from Jinshan Branch of Shanghai Sixth People's Hospital, 115 cases of which with cerebral infarction and 86 without it. Clinical tests were performed including coagulation indices, fasting glucose, serum lipid, and blood rheology. Logistic regression analyses were used to identify the risk factors. Regression model was established, and receiver operating characteristic (ROC) curve was applied to analyze its diagnostic value. RESULTS: Our data indicated that apolipoprotein AI (OR = 0.051, 95% CI: 0.009-0.295), lipoprotein (a) (OR = 1.003, 95% CI: 1.001-1.005), and RBC rigidity index (OR = 0.383, 95% CI: 0.209-0.702) were independent risk factors. Area under the curve (AUC) of the regression model = 0.78, with the sensitivity of 73.9% (95% CI: 64.9%-81.7%) and specificity of 69.2% (95% CI: 52.4%-83.0%). Prediction probability was determined while logistic regression score >0.748 defaulted as high-risk status. High-risk ratios were 80% in progressive cerebral infarction and 72% in nonprogressive cerebral infarction (P > .05), respectively, while significant differences were found when both compared with controls (P < .001). CONCLUSIONS: We show herein that the regression model based on apolipoprotein AI, lipoprotein (a), and RBC IR is a promising tool to predict the occurrence of cerebral infarction in patients with carotid artery stenosis. However, identification of novel diagnostic markers for progressive cerebral infarction is still necessary.

Recent advances in applying G-quadruplex for SARS-CoV-2 targeting and diagnosis: A review.

The coronavirus SARS-CoV-2 has caused a health care crisis all over the world since the end of 2019. Although vaccines and neutralizing antibodies have been developed, rapidly emerging variants usually display stronger immune escape ability and can better surpass vaccine protection. Therefore, it is still vital to find proper treatment strategies. To date, antiviral drugs against SARS-CoV-2 have mainly focused on proteases or polymerases. Notably, noncanonical nucleic acid structures called G-quadruplexes (G4s) have been identified in many viruses in recent years, and numerous G4 ligands have been developed. During this pandemic, literature on SARS-CoV-2 G4s is rapidly accumulating. Here, we first summarize the recent progress in the identification of SARS-CoV-2 G4s and their intervention by ligands. We then introduce the potential interacting proteins of SARS-CoV-2 G4s from both the virus and the host that may regulate G4 functions. The innovative strategy to use G4s as a diagnostic tool in SARS-CoV-2 detection is also reviewed. Finally, we discuss some key questions to be addressed in the future.

Targeting the RNA G-Quadruplex and Protein Interactome for Antiviral Therapy.

In recent years, G-quadruplexes (G4s), types of noncanonical four-stranded nucleic acid structures, have been identified in many viruses that threaten human health, such as HIV and Epstein-Barr virus. In this context, G4 ligands were designed to target the G4 structures, among which some have shown promising antiviral effects. In this Perspective, we first summarize the diversified roles of RNA G4s in different viruses. Next, we introduce small-molecule ligands developed as G4 modulators and highlight their applications in antiviral studies. In addition to G4s, we comprehensively review the medical intervention of G4-interacting proteins from both the virus (N protein, viral-encoded helicases, severe acute respiratory syndrome-unique domain, and Epstein-Barr nuclear antigen 1) and the host (heterogeneous nuclear ribonucleoproteins, RNA helicases, zinc-finger cellular nucelic acid-binding protein, and nucleolin) by inhibitors as an alternative way to disturb the normal functions of G4s. Finally, we discuss the challenges and opportunities in G4-based antiviral therapy.

Telomeric Recombination Induced by DNA Damage Results in Telomere Extension and Length Heterogeneity.

About 15% of human cancers counteract telomere loss by alternative lengthening of telomeres (ALT), which is attributed to homologous recombination (HR)-mediated events. But how telomeric HR leads to length elongation is poorly understood. Here, we explore telomere clustering and telomeric HR induced by double-stranded breaks (DSBs). We show that telomere clustering could occur at G1 and S phase of cell cycle and that three types of telomeric HR occur based on the manner of telomeric DNA exchange: equivalent telomeric sister chromatin exchange (T-SCE), inequivalent T-SCE, and No-SCE. While inequivalent T-SCE increases telomere length heterogeneity with no net gain of telomere length, No-SCE, which is presumably induced by interchromatid HR and/or break-induced replication, results in telomere elongation. Accordingly, cells subjected to long-term telomeric DSBs display increased heterogeneity of length and longer telomeres. We also demonstrate that DSBs-induced telomere elongation is telomerase independent. Moreover, telomeric recombination induced by DSBs is associated with formation of ALT-associated PML body and C-circle. Thus, DNA damage triggers recombination mediated elongation, leading to the induction of multiple ALT phenotypes.

Homologous recombination-dependent repair of telomeric DSBs in proliferating human cells.

Telomeres prevent chromosome ends from being recognized as double-stranded breaks (DSBs). Meanwhile, G/C-rich repetitive telomeric DNA is susceptible to attack by DNA-damaging agents. How cells balance the need to protect DNA ends and the need to repair DNA lesions in telomeres is unknown. Here we show that telomeric DSBs are efficiently repaired in proliferating cells, but are irreparable in stress-induced and replicatively senescent cells. Using the CRISPR-Cas9 technique, we specifically induce DSBs at telomeric or subtelomeric regions. We find that DSB repair (DSBR) at subtelomeres occurs in an error-prone manner resulting in small deletions, suggestive of NHEJ. However, DSBR in telomeres involves 'telomere-clustering', 3'-protruding C-rich telomeric ssDNA, and HR between sister-chromatid or interchromosomal telomeres. DSBR in telomeres is suppressed by deletion or inhibition of Rad51. These findings reveal proliferation-dependent DSBR in telomeres and suggest that telomeric HR, which is normally constitutively suppressed, is activated in the context of DSBR.