Advances on the regulation of telomerase.

Telomerase is composed of the catalytic subunit TERT (Telomerase reverse transcriptase),RNA subunit TERC (Telomerase RNA component) and other telomerase associated proteins. These two compartments with other telomerase subunits can assemble a holoenzyme, which maintain the length of telomeres. Telomerase plays important roles in cell senescence and tumor formation. The molecular mechanisms of the regulation of telomerase are very complicated. These processes comprise the regulation of transcription, post-transcription, post-translation and subcellular localization. Trafficking and assemble of TERT and TERC, as well as recruitment to telomeres, are also involved in this process. Here we review the regulation mechanism of telomerase from these aspects, and aim to laid a foundation for telomerase associated research and the drug targeting the telomerase.

Methyltransferase-like 17 physically and functionally interacts with estrogen receptors.

Estrogen exerts its physiological and pathological functions through two estrogen receptors (ERs), ERα and ERß, which act as transcription factors. Coregulators, including coactivators and corepressors, have been shown to be crucial for regulation of ER transcriptional activity. Although many coregulators have been identified to regulate activities of ERs, novel coregulators are still needed to be investigated. Here, we show that human methyltransferase-like 17 (METTL17), whose function is unknown, physically interacts with ERα and ERß, and functionally acts as a coactivator for ERs. METTL17 interacts with ER in vitro and in yeast and mammalian cells. Activation function-1 (AF1) and AF2 domains of ERs are responsible for the interaction between METTL17 and ERs. Knockdown of METTL17 reduces transcriptional activities of ERα and ERß in breast cancer cells, whereas METTL17 overexpression increases ERα and ERß transcriptional activities. Inhibition of METTL17 expression decreases mRNA and protein levels of ER target genes, including PR, cathepsin D, and pS2. Moreover, METTL17 knockdown reduces breast cancer cell growth. These results indicate that METTL17 is a novel coactivator of ERs and may play a role in breast tumorigenesis.

tRF-Gln-CTG-026 ameliorates liver injury by alleviating global protein synthesis.

tsRNAs (tRNA-derived small RNAs), as products of the stress response, exert considerable influence on stress response and injury regulation. However, it remains largely unclear whether tsRNAs can ameliorate liver injury. Here, we demonstrate the roles of tsRNAs in alleviating liver injury by utilizing the loss of NSun2 (NOP2/Sun domain family, member 2) as a tsRNAs-generating model. Mechanistically, the loss of NSun2 reduces methyluridine-U5 (m5U) and cytosine-C5 (m5C) of tRNAs, followed by the production of various tsRNAs, especially Class I tsRNAs (tRF-1s). Through further screening, we show that tRF-Gln-CTG-026 (tG026), the optimal tRF-1, ameliorates liver injury by repressing global protein synthesis through the weakened association between TSR1 (pre-rRNA-processing protein TSR1 homolog) and pre-40S ribosome. This study indicates the potential of tsRNA-reduced global protein synthesis in liver injury and repair, suggesting a potential therapeutic strategy for liver injury.

Effect of Dose Ratio on Mitoxantrone and Daunorubicin in Acute Myeloid Leukemia: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

PURPOSE: To investigate the effects of mitoxantrone and daunorubicin in induced chemotherapy on complete remission (CR), death during induction therapy, overall survival (OS), disease-free survival (DFS), and relapse in patients of all ages with acute myeloid leukemia (AML). METHODS: We searched published reports at the Medline, Embase, and Cochrane Databases as well as other databases from inception through July 2019. There was no restriction on date of publication or language (PROSPERO registration CRD42018095843). RESULTS: We enrolled 12 randomized controlled trials that included data of 4583 AML patients whose disease was untreated or relapsed/refractory, and compared the CR, death during induction therapy, DFS, and OS between mitoxantrone and daunorubicin. Mitoxantrone significantly increased the CR rate (relative risk = 1.07; 95% confidence interval [CI], 1.01, 1.14; P = .03) and DFS (hazard ratio = 0.87; 95% CI, 0.79, 0.96; P = .005) compared to daunorubicin. However, there was no significant difference in death during induction therapy (relative risk = 1.00; 95% CI, 0.81, 1.24; P = .99) and OS (hazard ratio = 0.94; 95% CI, 0.87, 1.01; P = .077) between the two drugs. CONCLUSION: Although more studies are needed to compare mitoxantrone with higher-dose daunorubicin, the results showed that compared to daunorubicin, mitoxantrone can significantly improve CR and DFS in patients of all ages. These findings suggest that mitoxantrone may be a better choice than daunorubicin as an induction chemotherapy agent for AML patients, especially in developing countries.

Transcriptional repression of p21 by EIF1AX promotes the proliferation of breast cancer cells.

OBJECTIVE: Dysregulation of the cell cycle is associated with the progression of malignant cancer, but its precise functional contribution is unknown. MATERIALS AND METHODS: The expression of EIF1AX in breast cancer tissues was detected by qRT-PCR and immunohistochemistry staining. Colony formation and tumour xenograft assays were used to examine the tumorigenesis-associated function of EIF1AX in vitro and in vivo. RNA-Seq analysis was used to select the downstream target genes of EIF1AX. Flow cytometry, ChIP and luciferase assays were used to investigate the molecular mechanisms by which EIF1AX regulates p21 in breast cancer cells. RESULTS: EIF1AX promoted breast cancer cell proliferation by promoting the G1/S cell cycle transition. A mechanistic investigation showed that EIF1AX inhibited the expression of p21, which is an essential cell cycle regulator. We identified that the transcriptional regulation of p21 by EIF1AX was p53-independent. Clinically, EIF1AX levels were significantly elevated in breast cancer tissues, and the high level of EIF1AX was associated with lower survival rates in breast cancer patients. CONCLUSIONS: Our results imply that EIF1AX may play a key role in the incidence and promotion of breast cancer and may, thus, serve as a valuable target for breast cancer therapy.

PES1 is a critical component of telomerase assembly and regulates cellular senescence.

Telomerase defers the onset of telomere shortening and cellular senescence by adding telomeric repeat DNA to chromosome ends, and its activation contributes to carcinogenesis. Telomerase minimally consists of the telomerase reverse transcriptase (TERT) and the telomerase RNA (TR). However, how telomerase assembles is largely unknown. Here, we demonstrate that PES1 (Pescadillo), a protein overexpressed in many cancers, forms a complex with TERT and TR through direct interaction with TERT, regulating telomerase activity, telomere length maintenance, and senescence. PES1 does not interact with the previously reported telomerase components Reptin, Pontin, p23, and Hsp90. PES1 facilitates telomerase assembly by promoting direct interaction between TERT and TR without affecting TERT and TR levels. PES1 expression correlates positively with telomerase activity and negatively with senescence in patients with breast cancer. Thus, we identify a previously unknown telomerase complex, and targeting PES1 may open a new avenue for cancer therapy.