Mismatch repair enzymes regulate telomere recombination in Saccharomycescerevisiae.

DNA mismatch repair (MMR) is a crucial mechanism that ensures chromosome stability and prevents the development of various human cancers. Apart from its role in correcting mismatches during DNA replication, MMR also plays a significant role in regulating recombination between non-identical sequences, a process known as homeologous recombination. Telomeres, the protective ends of eukaryotic chromosomes, possess sequences that are not perfectly homologous.

EGFR suppression contributes to growth inhibitory activity of G-quadruplex ligands in non-small cell lung cancers.

Non-small cell lung carcinomas (NSCLCs) commonly harbor activating mutations in the epidermal growth factor receptor (EGFR). Drugs targeting the tyrosine kinase activity of EGFR have shown effectiveness in inhibiting the growth of cancer cells with EGFR mutations. However, the development of additional mutations in cancer cells often leads to the persistence of the disease, necessitating alternative strategies to overcome this challenge.

Suppressing c-FOS expression by G-quadruplex ligands inhibits osimertinib-resistant non-small cell lung cancer.

Background: Osimertinib is the first-line therapy for patients with non-small cell lung cancer harboring epidermal growth factor receptor-activating alterations. Although osimertinib has been shown to elicit profound patient responses, cancer cells frequently develop additional alterations that sustain their proliferation capacity. This acquired resistance represents a substantial hurdle in precision medicine for patients with lung cancer.

Flap endonuclease Rad27 cleaves the RNA of R-loop structures to suppress telomere recombination.

The long non-coding telomeric RNA transcript TERRA, in the form of an RNA-DNA duplex, regulates telomere recombination. In a screen for nucleases that affects telomere recombination, mutations in DNA2, EXO1, MRE11 and SAE2 cause severe delay in type II survivor formation, indicating that type II telomere recombination is mediated through a mechanism similar to repairing double-strand breaks. On the other hand, mutation in RAD27 results in early formation of type II recombination, suggesting that RAD27 acts as a negative regulator in telomere recombination.

Unveiling a novel serpinB2-tripeptidyl peptidase II signaling axis during senescence.

Tripeptidyl peptidase II (TPPII or TPP2) degrades N-terminal tripeptides from proteins and peptides. Studies in both humans and mice have shown that TPPII deficiency is linked to cellular immune-senescence, lifespan regulation and the aging process. However, the mechanism of how TPPII participates in these processes is less clear.

Sequential Phosphorylation of Hepatitis C Virus NS5A Protein Requires the ATP-Binding Domain of NS3 Helicase.

The propagation of the hepatitis C virus (HCV) is regulated in part by the phosphorylation of its nonstructural protein NS5A that undergoes sequential phosphorylation on several highly conserved serine residues and switches from a hypo- to a hyperphosphorylated state. Previous studies have shown that NS5A sequential phosphorylation requires NS3 encoded on the same NS3-NS4A-NS4B-NS5A polyprotein. Subtle mutations in NS3 without affecting its protease activity could affect NS5A phosphorylation.

Dynamic DNA Shortening by Telomere-Binding Protein Cdc13.

Telomeres are essential for chromosome maintenance. Cdc13 is a single-stranded telomeric DNA binding protein that caps telomeres and regulates telomerase function in yeast. Although specific binding of Cdc13 to telomeric DNA is critical for telomere protection, the detail mechanism how Cdc13-DNA complex protects telomere is unclear.

CDC25B induces cellular senescence and correlates with tumor suppression in a p53-dependent manner.

The phosphatase cell division cycle 25B (Cdc25B) regulates cell cycle progression. Increased Cdc25B levels are often detected in cancer cell lines and human cancers and have been implicated in contributing to tumor growth, potentially by providing cancer cells with the ability to bypass checkpoint controls. However, the specific mechanism by which increased Cdc25B impacts tumor progression is not clear.

H3K4 methylation at active genes mitigates transcription-replication conflicts during replication stress.

Transcription-replication conflicts (TRCs) occur when intensive transcriptional activity compromises replication fork stability, potentially leading to gene mutations. Transcription-deposited H3K4 methylation (H3K4me) is associated with regions that are susceptible to TRCs; however, the interplay between H3K4me and TRCs is unknown. Here we show that H3K4me aggravates TRC-induced replication failure in checkpoint-defective cells, and the presence of methylated H3K4 slows down ongoing replication.

A Low-Toxicity DNA-Alkylating N-Mustard-Quinoline Conjugate with Preferential Sequence Specificity Exerts Potent Antitumor Activity Against Colorectal Cancer.

Efficacy and safety are fundamental prerequisites for anticancer drug development. In the present study, we explored the anti-colorectal cancer (CRC) activity of SL-1, a DNA-directed N-mustard-quinoline conjugate. The N-mustard moiety in SL-1 induced DNA strand breaks, interstrand cross-links (ICLs), G2/M arrest, and apoptosis, whereas its quinoline moiety preferentially directed SL-1 to target the selective guanine sequence 5'-G-G/C-N-G-C/T-3'.

The serine protease inhibitor serpinB2 binds and stabilizes p21 in senescent cells.

SerpinB2 is a serine protease inhibitor also known as plasminogen activator inhibitor type 2 (PAI-2). It has been well documented that serpinB2 is an inhibitor of urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA). Interestingly, serpinB2 levels are increased in senescent cells and serpinB2 is thus considered a senescence biomarker.

Modulation of yeast telomerase activity by Cdc13 and Est1 in vitro.

Telomerase is the enzyme involved in extending telomeric DNA. Control of telomerase activity by modulating its access to chromosome ends is one of the most important fundamental mechanisms. This study established an in vitro yeast telomerase reconstitution system that resembles telomere replication in vivo.

Identification of a new class of WNT1 inhibitor: Cancer cells migration, G-quadruplex stabilization and target validation.

Developing the Wnt pathway inhibitors has been considered as a therapeutic approach for cancers and other Wnt-related diseases. Previously we found that the G-rich sequence of WNT1 promoter is capable of forming G-quadruplex structure and stabilizing agents for Wnt1-mediated signaling pathway. Using a established cell-based drug screen system that enabled the evaluation of WNT1 expression activity in a G-quadruplex structure dependent manner, we evaluated a series of 6-substituted 9-chloro-11H-indeno[1,2-c]quinolin-11-one derivatives that potentially inhibit the Wnt1-mediated signaling pathway.

Direct evidence of mitochondrial G-quadruplex DNA by using fluorescent anti-cancer agents.

G-quadruplex (G4) is a promising target for anti-cancer treatment. In this paper, we provide the first evidence supporting the presence of G4 in the mitochondrial DNA (mtDNA) of live cells. The molecular engineering of a fluorescent G4 ligand, 3,6-bis(1-methyl-4-vinylpyridinium) carbazole diiodide (BMVC), can change its major cellular localization from the nucleus to the mitochondria in cancer cells, while remaining primarily in the cytoplasm of normal cells.

A Fluorescent Anti-Cancer Agent, 3,6-bis(1-methyl-4-vinylpyridinium) Carbazole Diiodide, Stains G-Quadruplexes in Cells and Inhibits Tumor Growth.

Compelling evidence suggests that formation of guanine-quadruplex (G4) can protect the integrity of chromosome ends in eukaryotes, and regulate the activity of some gene promoters. In addition, G4 may be a novel therapeutic target. Thus, a number of ligands have been synthesized to stabilize G4.

The addition of a spin column step in the telomeric repeat application protocol removes telomerase inhibitors.

Telomerase activity in cancer cells is commonly analyzed by a polymerase chain reaction (PCR)-based assay termed the telomeric repeat amplification protocol (TRAP). However, nonspecific inhibition of Taq polymerase during the PCR step is frequently observed in inhibitor analysis or drug screening. Thus, the removal of excess inhibitors prior to PCR is an essential step for the proper evaluation of telomerase inhibitory effects.

Conformational transition of a hairpin structure to G-quadruplex within the WNT1 gene promoter.

The role of G-quadruplexes (G4s) in biological systems has been widely studied. It is found that they have an important function in gene transcription and regulation. In this work, we have identified two topologies of hairpin and G4 structures formed by a native G-rich sequence (WT22: 5'-GGGCCACCGGGCAGGGGGCGGG-3') from the WNT1 promoter region using nuclear magnetic resonance (NMR) spectroscopy.

Pif1 regulates telomere length by preferentially removing telomerase from long telomere ends.

Telomerase, a ribonucleoprotein complex, is responsible for maintaining the telomere length at chromosome ends. Using its RNA component as a template, telomerase uses its reverse transcriptase activity to extend the 3'-end single-stranded, repetitive telomeric DNA sequence. Pif1, a 5'-to-3' helicase, has been suggested to regulate telomerase activity.

Yin Yang 1 is a target of microRNA-34 family and contributes to gastric carcinogenesis.

Gastric cancer is the second leading cause of cancer-related death worldwide. Herein, we investigated the role of transcription factor Yin Yang 1 (YY1), a multi-functional protein, in tumorigenesis of gastric cancer cells. Results showed that YY1 contributed to gastric carcinogenesis of SC-M1 cells including growth, viability, and abilities of colony formation, migration, invasion, and tumorsphere formation.

Inhibition of cancer cell migration and invasion through suppressing the Wnt1-mediating signal pathway by G-quadruplex structure stabilizers.

WNT1 encodes a multifunctional signaling glycoprotein that is highly expressed in several malignant tumors. Patients with Wnt1-positive cancer are usually related to advanced metastasis. Here, we found that a stretch of G-rich sequences located at the WNT1 promoter region is capable of forming G-quadruplex structures.

Telomeric transcripts stimulate telomere recombination to suppress senescence in cells lacking telomerase.

In human somatic cells or yeast cells lacking telomerase, telomeres are shortened upon each cell division. This gradual shortening of telomeres eventually leads to senescence. However, a small population of telomerase-deficient cells can survive by bypassing senescence through the activation of alternative recombination pathways to maintain their telomeres.

Structure-based design, synthesis and biological evaluation of novel anthra[1,2-d]imidazole-6,11-dione homologues as potential antitumor agents.

By using fragment-based design strategies, a series of 2-thio-substituted anthra[1,2-d]imidazole-6,11-diones were synthesized and evaluated for hTERT repressing activities, cell proliferations, and NCI 60-cell panel assay. Compounds 2, 3, 4, 11, 15 and 35 were selected by the NCI and 3, 4, 11 and 15 represent the GI₅₀, TGI and LC₅₀, respectively. Among them, all were moderate selectivity toward leukemia cancer except for 4 exhibited distinctive selectivity of CNS and renal cancer with 7.

Development and evaluation of novel phosphotyrosine mimetic inhibitors targeting the Src homology 2 domain of signaling lymphocytic activation molecule (SLAM) associated protein.

Specific interactions between Src homology 2 (SH2) domain-containing proteins and the phosphotyrosine-containing counterparts play significant role in cellular protein tyrosine kinase (PTK) signaling pathways. The SH2 domain inhibitors could potentially serve as drug candidates in treating human diseases. Here we have incorporated a novel phosphotyrosine mimetic, which is an unusual amino acid carrying a cyclosaligenyl (cycloSal) phosphodiester moiety, into dipeptides to investigate the inhibitory effect on SH2 domain-containing proteins.