BER pathway

BACKGROUND: Lung cancer is a major cause of cancer-related mortality worldwide, with a 5-year survival rate of approximately 22%. Cisplatin is one of the standard first-line chemotherapeutic agents for non-small cell lung cancer (NSCLC), but its efficacy is often limited by the development of resistance. Despite extensive research on the molecular mechanisms of chemoresistance, the underlying causes remain elusive and complex. AIMS: We analyzed three microarray datasets to find the gene signature and key pathways related to cisplatin resistance in NSCLC...

Maintaining genomic stability and properly repairing damaged DNA is essential to staying healthy and preserving cellular homeostasis. The five major pathways involved in repairing eukaryotic DNA include base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), non-homologous end joining (NHEJ), and homologous recombination (HR). When these pathways do not properly repair damaged DNA, genomic stability is compromised and can contribute to diseases such as cancer. It is essential that the causes of DNA damage and the consequent repair pathways are fully understood, yet the initial recruitment and regulation of DNA damage response proteins remains unclear...

Photobiomodulation (PBM) induced by non-ionizing radiations emitted from low-power lasers and light-emitting diodes (LEDs) has been used for various therapeutic purposes due to its molecular, cellular, and systemic effects. At the molecular level, experimental data have suggested that PBM modulates base excision repair (BER), which is responsible for restoring DNA damage. There is a relationship between the misfunction of the BER DNA repair pathway and the development of tumors, including breast cancer. However, the effects of PBM on cancer cells have been controversial...

The NTHL1 and NEIL1-3 DNA glycosylases are major enzymes in the removal of oxidative DNA base lesions, via the base excision repair (BER) pathway. It is expected that lack of these DNA glycosylases activities would render cells vulnerable to oxidative stress, promoting cell death. Intriguingly, we found that single, double, triple, and quadruple DNA glycosylase knockout HAP1 cells are, however, more resistant to oxidative stress caused by genotoxic agents than wild type cells. Furthermore, glutathione depletion in NEIL deficient cells further enhances resistance to cell death induced via apoptosis and ferroptosis...

ETHNOPHARMACOLOGICAL RELEVANCE: Jiao-tai-wan (JTW), a classic herbal formula of traditional Chinese medicine recorded in Han Shi Yi Tong, has been used to alleviate sleep disorders since ancient times. In modern pharmacological research, JTW has been adopted for treating diabetes mellitus and even exerts antidepressant effects. However, the potential mechanisms deserve further elucidation. AIM OF THE STUDY: The prevalence of diabetes mellitus combined with depressive disorder (DD) is continuing to increase, yet it is currently under-recognized and its treatment remains inadequate...

Neurodevelopment is a tightly coordinated process, during which the genome is exposed to spectra of endogenous agents at different stages of differentiation. Emerging evidence indicates that DNA damage is an important feature of developing brain, tightly linked to gene expression and neuronal activity. Some of the most frequent DNA damage includes changes to DNA bases, which are recognized by DNA glycosylases and repaired through base excision repair (BER) pathway. The only mammalian DNA glycosylase able to remove frequent alkylated DNA based is alkyladenine DNA glycosylase (Aag, aka Mpg)...

Long-term spaceflights affect the structural changes in brain, alter motor or cognitive function and associated development of neuro-optic syndrome in astronauts. Studies addressing the impact of microgravity on brain cells are very limited. Herein, we employed microglial (CHME3) and glioblastoma (U87MG and A172) cells to study their molecular and functional adaptations under simulated microgravity (SMG) exposure. A reduction in cell viability and proliferation with decreased levels of PCNA were observed in these cells...

Acetaldehyde is the primary metabolite of alcohol and is present in many environmental sources including tobacco smoke. Acetaldehyde is genotoxic, whereby it can form DNA adducts and lead to mutagenesis. Individuals with defects in acetaldehyde clearance pathways have increased susceptibility to alcohol-associated cancers. Moreover, a mutation signature specific to acetaldehyde exposure is widespread in alcohol and smoking-associated cancers. However, the pathways that repair acetaldehyde-induced DNA damage and thus prevent mutagenesis are vaguely understood...

UNLABELLED: The large majority of oxidative DNA lesions occurring in the G1 phase of the cell cycle are repaired by base excision repair (BER) rather than mismatch repair (MMR) to avoid long resections that can lead to genomic instability and cell death. However, the molecular mechanisms dictating pathway choice between MMR and BER have remained unknown. Here, we show that, during G1, D-type cyclins are recruited to sites of oxidative DNA damage in a PCNA- and p21-dependent manner. D-type cyclins shield p21 from its two ubiquitin ligases CRL1 SKP2 and CRL4 CDT2 in a CDK4/6-independent manner...

O6 -methylguanine-DNA methyltransferase (MGMT or AGT) is a DNA repair protein with the capability to remove alkyl groups from O6 -AlkylG adducts. Moreover, MGMT plays a crucial role in repairing DNA damage induced by methylating agents like temozolomide and chloroethylating agents such as carmustine, and thereby contributes to chemotherapeutic resistance when these agents are used. This review delves into the structural roles and repair mechanisms of MGMT, with emphasis on the potential structural and functional roles of the N-terminal domain of MGMT...

To characterize the hits from a phenotypic neurotoxicity screen, we obtained transcriptomics data for valinomycin, diethylstilbestrol, colchicine, rotenone, 1-methyl-4-phenylpyridinium (MPP), carbaryl and berberine (Ber). For all compounds, the concentration triggering neurite degeneration correlated with the onset of gene expression changes. The mechanistically diverse toxicants caused similar patterns of gene regulation: the responses were dominated by cell de-differentiation and a triggering of canonical stress response pathways driven by ATF4 and NRF2...

The circadian-controlled DNA repair exhibits a strong diurnal rhythm. Disruption in circadian clock and DNA repair is closely linked with hepatocellular carcinoma (HCC) progression, but the mechanism remains unknown. Here, we show that polymerase beta (POLB), a critical enzyme in the DNA base excision repair pathway, is rhythmically expressed at the translational level in mouse livers. Hepatic POLB dysfunction dampens clock homeostasis, whereas retards HCC progression, by mediating the methylation of the 4th CpG island on the 5'UTR of clock gene Per1...

Oxidative stress-induced DNA base modifications, if unrepaired, can increase mutagenesis and genomic instability, ultimately leading to cell death. Cells predominantly use the base excision repair (BER) pathway to repair oxidatively-induced non-helix distorting lesions. BER is initiated by DNA glycosylases, such as 8-oxoguanine DNA glycosylase (OGG1), which repairs oxidatively modified guanine bases, including 7,8-dihydro-8-oxoguanine (8-oxoG) and ring-opened formamidopyrimidine lesions, 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG)...

Ten-Eleven-Translocase (TET) enzymes contribute to the regulation of the methylome via successive oxidation of 5-methyl cytosine (5mC) to derivatives which can be actively removed by base-excision-repair (BER) mechanisms in the absence of cell division. This is particularly important in post-mitotic neurons where changes in DNA methylation are known to associate with changes in neural function. TET3, specifically, is a critical regulator of both neuronal differentiation in development and mediates dynamic changes in the methylome of adult neurons associated with cognitive function...

Mammalian polynucleotide kinase 3'-phosphatase (PNKP), a DNA end-processing enzyme with 3'-phosphatase and 5'-kinase activities, is involved in multiple DNA repair pathways, including base excision (BER), single-strand break (SSBR), and double-strand break repair (DSBR). However, little is known as to how PNKP functions in such diverse repair processes. Here we report that PNKP is acetylated at K142 (AcK142) by p300 constitutively but at K226 (AcK226) by CBP, only after DSB induction. Co-immunoprecipitation analysis using AcK142 or AcK226 PNKP-specific antibodies showed that AcK142-PNKP associates only with BER/SSBR, and AcK226 PNKP with DSBR proteins...

Deficiency of DNA repair pathways drives the development of colorectal cancer. However, the role of the base excision repair (BER) pathway in colorectal cancer initiation remains unclear. This study shows that Nei-like DNA glycosylase 1 (NEIL1) is highly expressed in colorectal cancer (CRC) tissues and associated with poorer clinical outcomes. Knocking out neil1 in mice markedly suppresses tumorigenesis and enhances infiltration of CD8+ T cells in intestinal tumors. Furthermore, NEIL1 directly forms a complex with SATB2/c-Myc to enhance the transcription of COL17A1 and subsequently promotes the production of immunosuppressive cytokines in CRC cells...

APE1/REF-1 (apurinic/apyrimidinic endonuclease 1 / redox factor-1) is a protein with two domains, with endonuclease function and redox activity. Its main activity described is acting in DNA repair by base excision repair (BER) pathway, which restores DNA damage caused by oxidation, alkylation, and single-strand breaks. In contrast, the APE1 redox domain is responsible for regulating transcription factors, such as AP-1 (activating protein-1), NF-κB (Nuclear Factor kappa B), HIF-1α (Hypoxia-inducible factor 1-alpha), and STAT3 (Signal Transducers and Activators of Transcription 3)...

Alectinib, a second-generation anaplastic lymphoma kinase (ALK) inhibitor, has been shown to be effective for patients with ALK-positive non-small cell lung cancer (NSCLC). However, alectinib resistance is a serious problem worldwide. To the best of our knowledge, little information is available on its molecular mechanisms using the Gene Expression Omnibus (GEO) database. In this study, the differentially expressed genes (DEGs) were selected from the gene expression profile GSE73167 between parental and alectinib-resistant human lung adenocarcinoma (LUAD) cell samples...

Base excision repair (BER) requires a coordination from gap filling by DNA polymerase (pol) β to subsequent nick sealing by DNA ligase IIIα at downstream steps of the repair pathway. X-ray cross-complementing protein 1 (XRCC1), a non-enzymatic scaffolding protein, forms repair complexes with polβ and DNA ligase (LIG) IIIα. Yet, the impact of the polβ mutations that affect XRCC1 interaction and protein stability on the repair pathway coordination during nick sealing by LIGIIIα remains unknown...

DNA is the major target of radiation therapy of malignant tumors. Ionizing radiation (IR) induces a variety of DNA lesions, including chemically modified bases and strand breaks. The use of proton beam therapy for cancer treatment is ramping up, as it is expected to reduce normal tissue damage. Thus, it is important to understand the molecular mechanisms of recognition, signaling, and repair of DNA damage induced by protons in the perspective of assessing not only the risk associated with human exposure to IR but also the possibility to improve the efficacy of therapy...