DNA repair

The metal-nucleic acid nanocomposites, first termed metal-nucleic acid frameworks (MNFs) in this work, show extraordinary potential as functional nanomaterials. However, thus far, realized MNFs face limitations including harsh synthesis conditions, instability, and non-targeting. Herein, we discover that longer oligonucleotides can enhance the synthesis efficiency and stability of MNFs by increasing oligonucleotide folding and entanglement probabilities during the reaction. Besides, longer oligonucleotides provide upgraded metal ions binding conditions, facilitating MNFs to load macromolecular protein drugs at room temperature...

Since US Food and Drug Administration approval of programmed death ligand 1 (PD-L1) as the first companion diagnostic for immune checkpoint inhibitors (ICIs) in non-small cell lung cancer, many patients have experienced increased overall survival. To improve selection of ICI responders versus nonresponders, microsatellite instability/mismatch repair deficiency (MSI/MMR) and tumor mutation burden (TMB) came into play. Clinical data show PD-L1, MSI/MMR, and TMB are independent predictive immunotherapy biomarkers...

Although gene conversion (GC) in Saccharomyces cerevisiae is the most error-free way to repair double-strand breaks (DSBs), the mutation rate during homologous recombination is 1000 times greater than during replication. Many mutations involve dissociating a partially- copied strand from its repair template and re-aligning with the same or another template, leading to -1 frameshifts in homonucleotide runs, quasipalindrome (QP)-associated mutations and microhomology-mediated interchromosomal template switches...

DNA damage is a critical factor in the onset and progression of cancer. When DNA is damaged, the number of genetic mutations increases, making it necessary to activate DNA repair mechanisms. A crucial factor in the base excision repair process, which helps maintain the stability of the genome, is an enzyme called DNA polymerase [Formula: see text] (Pol[Formula: see text]) encoded by the POLB gene. It plays a vital role in the repair of damaged DNA. Additionally, variations known as Single Nucleotide Polymorphisms (SNPs) in the POLB gene can potentially affect the ability to repair DNA...

Amino acid bioavailability impacts mRNA translation in a codon-dependent manner. Here, we report that the anti-cancer MAPK inhibitors (MAPKi) decrease the intracellular concentration of aspartate and glutamate in melanoma cells. This coincides with the accumulation of ribosomes on codons corresponding to these amino acids and triggers the translation-dependent degradation of mRNAs encoding aspartate- and glutamate-rich proteins, involved in DNA metabolism such as DNA replication and repair. Consequently, cells that survive MAPKi degrade aspartate and glutamate likely to generate energy, which simultaneously decreases their requirement for amino acids due to the downregulation of aspartate- and glutamate-rich proteins involved in cell proliferation...

The USP7 deubiquitinase regulates proteins involved in the cell cycle, DNA repair, and epigenetics and has been implicated in cancer progression. USP7 inhibition has been pursued for the development of anti-cancer therapies. Here, we describe the discovery of potent and specific USP7 inhibitors exemplified by FX1-5303. FX1-5303 was used as a chemical probe to study the USP7-mediated regulation of p53 signaling in cells. It demonstrates mechanistic differences compared to MDM2 antagonists, a related class of anti-tumor agents that act along the same pathway...

BACKGROUND: Sarcopenia is characterized by loss of skeletal muscle mass and function, and is a major risk factor for disability and independence in the elderly. Effective medication is not available. Dietary restriction (DR) has been found to attenuate aging and aging-related diseases, including sarcopenia, but the mechanism of both DR and sarcopenia are incompletely understood. METHODS: In this study, mice body weight, fore and all limb grip strength, and motor learning and coordination performance were first analysed to evaluate the DR effects on muscle functioning...

BACKGROUND: The DNA-dependent protein kinase (DNA-PK) complex comprises a catalytic (PRKDC) and two requisite DNA-binding (Ku70/Ku80) subunits. The role of the complex in repairing double-stranded DNA breaks (DSBs) is established, but its role in inflammation, as a complex or individual subunits, remains elusive. While only ~ 1% of PRKDC is necessary for DNA repair, we reported that partial inhibition blocks asthma in mice without causing SCID. METHODS: We investigated the central role of PRKDC in inflammation and its potential association with DNA repair...

The BRCA1 carboxyl-terminal (BRCT) domain, an evolutionarily conserved structural motif, is ubiquitous in a multitude of proteins spanning prokaryotic and eukaryotic organisms. In Mycobacterium tuberculosis (Mtb), BRCT domain plays a pivotal role in the catalytic activity of the NAD+-dependent DNA ligase (LigA). LigA is pivotal in DNA replication, catalyzing the formation of phosphodiester bonds in Okazaki fragments and repairing single-strand breaks in damaged DNA, essential for the survival of Mtb. Structural and functional aspects of LigA unveil its character as a highly modular protein, undergoing substantial conformational changes during its catalytic cycle...

CUL4B, a crucial scaffolding protein in the largest E3 ubiquitin ligase complex CRL4B, is involved in a broad range of physiological and pathological processes. While previous research has shown that CUL4B participates in maintaining intestinal homeostasis and function, its involvement in facilitating intestinal recovery following ionizing radiation (IR) damage has not been fully elucidated. Here, we utilized in vivo and in vitro models to decipher the role of CUL4B in intestinal repair after IR-injury. Our findings demonstrated that prior to radiation exposure, CUL4B inhibited the ubiquitination modification of PSME3, which led to the accumulation of PSME3 and subsequent negative regulation of p53-mediated apoptosis...

Fanconi Anemia (FA) pathway resolves DNA interstrand cross links (ICL). The FA pathway was initially recognized in vertebrates, but was later confirmed in other animals and speculated in fungi. FA proteins FANCM, FANCL and FANCJ are present in Saccharomyces cerevisiae but, their mechanism of interaction to resolve ICL is still unclear. Unlike Dikarya, early diverging fungi (EDF) possess more traits shared with animals. We traced the evolutionary history of the FA pathway across Opisthokonta. We scanned complete proteomes for FA-related homologs to establish their taxonomic distribution and analyzed their phylogenetic trees...

Alterations of bases in DNA constitute a major source of genomic instability. It is believed that base alterations trigger base excision repair (BER), generating DNA repair intermediates interfering with DNA replication. Here, we show that genomic uracil, a common type of base alteration, induces DNA replication stress (RS) without being processed by BER. In the absence of uracil DNA glycosylase (UNG), genomic uracil accumulates to high levels, DNA replication forks slow down, and PrimPol-mediated repriming is enhanced, generating single-stranded gaps in nascent DNA...

Although certain members of the Ubiquitin-specific peptidases (USPs) have been recognized as promising therapeutic targets for various diseases, research progress regarding USP21 has been relatively sluggish in its early stages. USP21 is a crucial member of the USPs subfamily, involved in diverse cellular processes such as apoptosis, DNA repair, and signal transduction. Research findings from the past decade demonstrate that USP21 mediates the deubiquitination of multiple well-known target proteins associated with critical cellular processes relevant to both disease and homeostasis, particularly in various cancers...

Cancer is caused by a complex interaction of factors that interrupt the normal growth and division of cells. At the center of this process is the intricate relationship between DNA damage and the cellular mechanisms responsible for maintaining genomic stability. When DNA damage is not repaired, it can cause genetic mutations that contribute to the initiation and progression of cancer. On the other hand, the DNA damage response system, which involves the phosphorylation of the histone variant H2AX (γH2AX), is crucial in preserving genomic integrity by signaling and facilitating the repair of DNA double-strand breaks...

The effectiveness of photodynamic therapy (PDT) has been greatly restricted by the hypoxic tumor microenvironment and the susceptible resistance of monotherapy. Although nanodrugs based on transition metal complexes capable of integrating PDT with photoactivated chemotherapy (PACT) have garnered tremendous attention as promising candidates for overcoming the above limitations, the therapeutic efficacy of these nanodrugs is still hampered by inadequate loading of active pharmaceutical ingredients (APIs) and the inherent ability of cancer cells to repair damaged DNA...

Spontaneous mutations are the ultimate source of novel genetic variation on which evolution operates. Although mutation rate is often discussed as a single parameter in evolution, it comprises multiple distinct types of changes at the level of DNA. Moreover, the rates of these distinct changes can be independently influenced by genomic background and environmental conditions. Using fluctuation tests, we characterized the spectrum of spontaneous mutations in Escherichia coli grown in low and high glucose environments...

The migration of an electron-loss center (hole) in calf thymus DNA to bisbenzimidazole ligands bound in the minor groove is followed by pulse radiolysis combined with time-resolved spectrophotometry. The initially observed absorption spectrum upon oxidation of DNA by the selenite radical is consistent with spin on cytosine (C), as the GC• pair neutral radical, followed by the spectra of oxidized ligands. The rate of oxidation of bound ligands increased with an increase in the ratio ( r ) ligands per base pair from 0...

DNA is susceptible to various factors in vitro and in vivo and experience different forms of damage,among which double-strand break(DSB)is a deleterious form.To maintain the stability of genetic information,organisms have developed multiple mechanisms to repair DNA damage.Among these mechanisms,homologous recombination(HR)is praised for the high accuracy.The MRE11-RAD50-NBS1(MRN)complex plays an important role in HR and is conserved across different species.The knowledge on the MRN complex mainly came from the previous studies in Saccharomyces cerevisiae and Caenorhabditis elegans ,while studies in the last decades have revealed the role of mammalian MRN complex in DNA repair of higher animals...

Objective To study the expression of SWI/SNF-related,matrix-associated,actin-dependent regulator of chromatin,subfamily A,member 4(SMARCA4)/Brahma-related gene 1,V-raf murine sarcoma viral oncogene homolog B(BRAF),P53,programmed cell death protein-1(PD-1),and programmed death-ligand 1(PD-L1),and changes in the expression of BRAF and neurotrophic tyrosine receptor kinase(NTRK) in the patients with colorectal cancer in Tibet,thereby providing a basis for targeted therapy and immunotherapy for this disease in Tibet...

BACKGROUND: Atherosclerosis, a leading cause of cardiovascular disease, involves the pathological activation of various cell types, including immunocytes (eg, macrophages and T cells), smooth muscle cells (SMCs), and endothelial cells. Accumulating evidence suggests that transition of SMCs to other cell types, known as phenotypic switching, plays a central role in atherosclerosis development and complications. However, the characteristics of SMC-derived cells and the underlying mechanisms of SMC transition in disease pathogenesis remain poorly understood...