Wenbin Ma

Senomorphic microRNAs (miRNAs) are a class of small regulatory RNAs that selectively suppress the senescence-associated secretory phenotype (SASP) without eliminating senescent cells, thereby offering a targeted approach to counteract the pro-tumorigenic consequences of therapy-induced senescence (TIS). Despite their therapeutic potential, senomorphic miRNAs in luminal breast cancer remain poorly characterized. Here, we performed small RNA sequencing to profile miRNA expression changes in a doxorubicin-induced TIS model using the luminal breast cancer line MCF7. We identified miR-3155b as a previously uncharacterized miRNA significantly downregulated during TIS. Functional studies revealed that miR-3155b overexpression suppressed the mRNA and protein levels of multiple SASP factors, including IL6, IL8 (CXCL8), MMP13, TNF, IL1B, and IFNB1, whereas its knockdown enhanced their expression. Critically, these effects occurred without affecting core senescence phenotypes such as proliferation arrest, SA-β-gal activity, or DNA damage foci formation. This senomorphic function was further confirmed in an ionizing radiation (IR)-induced TIS model and in T47D luminal breast cancer cells. miR-3155b was confirmed to target the CXCL8 mRNA by luciferase reporter assays, and RNA pull-down assays indicated that miR-3155b physically associates with IFNB1 , IL6 , TNF , and MMP13 mRNAs. Collectively, our findings identify miR-3155b as a senomorphic miRNA in Luminal A breast cancer TIS and provide a potential target for optimizing chemoradiotherapy strategies aimed at mitigating SASP-driven adverse effects.

NME1 is a key metastasis suppressor whose activity depends on histidine phosphorylation, yet the biological significance of this modification remains poorly understood. Here, we reveal a previously unrecognized role for NME1 in regulating the Hippo pathway. Using PhastID-based proximity labeling combined with functional assays, we demonstrate that NME1 modulates CDC42 activity via ARHGAP17, a GTPase-activating protein, thereby influencing cytoskeletal organization and Hippo activation. Loss of NME1 reduced YAP phosphorylation and promoted its nuclear localization, indicating suppression of Hippo signaling. These findings define a histidine phosphorylation-dependent NME1–ARHGAP17–CDC42–cytoskeleton axis that controls the Hippo pathway, providing new insights into the functional repertoire of NME1 in cancer and development.

Nuclear condensates (NCs) are membraneless organelles that enable spatial and functional compartmentalization in the nucleus. Yet, the components and functional co-organization of NCs have been poorly studied. Here, we used PhastID to explore the proximal interactome of 18 NCs in HeLa cells. Our data revealed the organizational flow of gene control among these NCs. Crucially, we developed an algorithm to dissect the intricate internal relations of NCs. This algorithm led to key discoveries: the identification of an uncharacterized BUD13 condensate, and the recognition of specific co-organizations between nuclear gems and Cajal bodies for telomerase maturation, and between nuclear gems and histone locus bodies for histone gene pre-mRNA processing. We also created a global reference map to understand NC dynamics under stresses and how disease-related mutations differentially affect NC interactomes. Overall, our work provides a proximal proteome-based atlas for human NCs, substantially advancing our spatiotemporal understanding of nuclear biological events.

小泛素相关修饰(SUMO)是一种翻译后修饰, 在多种生理病理过程中发挥关键作用.SUMO蛋白通过共价键和非共价键的方式与靶蛋白相互作用, 分别称为SUMO化修饰和SUMO非共价结合.大多数研究关注SUMO化修饰, 而对于作用力弱且短暂的SUMO结合, 特别是同时检测SUMO化修饰和 SUMO结合的研究都十分缺乏.为了克服这一限制, 我们基于双分子荧光互补实验(BiFC)和深度学习算法DeepSUMO, 开发了一个同时鉴定SUMO化修饰和SUMO非共价结合靶蛋白的高通量流程. 通过这个流程, 我们成功鉴定了1379个非共价和8457个共价SUMO调控靶蛋白, 其中超过70% 是首次鉴定到的.我们的研究结果突出了SUMO化修饰和SUMO非共价结合的关键调控作用, 可为未来SUMO作用的研究提供宝贵的资源.DeepSUMO已被开发为一个在线工具(http://deepsumo.renlab.org)供其他研究者使用.

Anti-aging functional foods benefit the elderly. Telomeres are chromosomal ends that maintain genome stability extended by telomerase catalytic subunit TERT. Due to the end-replication problem, telomeres shorten after each cell cycle without telomerase in most human cells, and eventually the cell enters the senescence stage. Natural products can attenuate the aging process by increasing telomerase activity, such as TA-65. However, TA-65 is expensive. Other Chinese natural products may achieve comparable effects. Here, we found that Rosa roxburghii fruit extracts effectively increase TERT expression and telomerase activity in cultured human mesenchymal stem cells. Both R. roxburghii fruit extracts obtained by freeze-drying and spray-drying increased the activity of telomerase. R. roxburghii fruit extracts were able to reduce reactive oxygen species levels, enhance superoxide dismutase activity, and reduce DNA damage caused by oxidative stress or radiation. R. roxburghii fruit extracts promoted cell proliferation, improved senescent cell morphology, delayed replicative cellular senescence, attenuated cell cycle suppressors, and alleviated the senescence-associated secretory phenotype. Transcriptome and metabolic profiling revealed that R. roxburghii fruit extracts promote DNA replication and telomere maintenance pathways and decrease triglyceride levels. Overall, we provide a theoretical basis for the application of R. roxburghii fruit as an anti-aging product.

Telomeres are specialized structures at the ends of linear chromosomes that protect genome stability. The telomeric repeat-containing RNA (TERRA) that is transcribed from subtelomeric regions can invade into double-stranded DNA regions and form RNA:DNA hybrid-containing structure called R-loop. In tumor cells, R-loop formation is closely linked to gene expression and the alternative lengthening of telomeres (ALT) pathway. Dysregulated R-loops can cause stalled replication forks and telomere instability. However, how R-loops are recognized and regulated, particularly at telomeres, is not well understood. We discovered that ILF3 selectively associates with telomeric R-loops and safeguards telomeres from abnormal homologous recombination. Knocking out ILF3 results in excessive R-loops at telomeres and triggers telomeric DNA damage responses. In addition, ILF3 deficiency disrupts telomere homeostasis and causes abnormalities in the ALT pathway. Using the proximity-dependent biotin identification (BioID) technology, we mapped the ILF3 interactome and discovered that ILF3 could interact with several DNA/RNA helicases, including DHX9. Importantly, ILF3 may aid in the resolution of telomeric R-loops through its interaction with DHX9. Our findings suggest that ILF3 may function as a reader of telomeric R-loops, helping to prevent abnormal homologous recombination and maintain telomere homeostasis.

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.

The importance of the network defined by phosphatidylinositol-3-kinase (PI3K), AKT and mammalian target of rapamycin (mTOR) downstream of Receptor Tyrosine Kinase (RTK) has been recognized for many years. However, the central role of RICTOR (rapamycin-insensitive companion of mTOR) in this pathway has only recently come to light. The function of RICTOR in pan-cancer still needs to be systematically elucidated. In this study, we examined RICTOR’s molecular characteristics and clinical prognostic value by pan-cancer analysis. Our findings indicate that RICTOR was overexpressed in twelve cancer types, and a high RICTOR expression was linked to poor overall survival. Moreover, the CRISPR Achilles’ knockout analysis revealed that RICTOR was a critical gene for the survival of many tumor cells. Function analysis revealed that RICTOR-related genes were mainly involved in TOR signaling and cell growth. We further demonstrated that the RICTOR expression was significantly influenced by genetic alteration and DNA-methylation in multiple cancer types. Additionally, we found a positive relationship between RICTOR expression and the immune infiltration of macrophages and cancer-associated fibroblasts in Colon adenocarcinoma and Head and Neck squamous cell carcinoma. Finally, we validated the ability of RICTOR in sustaining tumor growth and invasion in the Hela cell line using cell-cycle analysis, the cell proliferation assay, and wound-healing assay. Our pan-cancer analysis highlights the critical role of RICTOR in tumor progression and its potential as a prognostic marker for various cancer types.