Human translesion DNA polymerases ι and κ mediate tolerance to temozolomide in MGMT-deficient glioblastoma cells.

Glioblastoma (GBM) is a highly aggressive brain tumor associated with poor patient survival. The current standard treatment involves invasive surgery, radiotherapy, and chemotherapy employing temozolomide (TMZ). Resistance to TMZ is, however, a major challenge.

RecQ helicase expression in patients with telomeropathies.

Background: Telomeropathies are a group of inherited disorders caused by germline pathogenic variants in genes involved in telomere maintenance, resulting in excessive telomere attrition that affects several tissues, including hematopoiesis. RecQ and RTEL1 helicases contribute to telomere maintenance by unwinding telomeric structures such as G-quadruplexes (G4), preventing replication defects. Germline RTEL1 variants also are etiologic in telomeropathies.

Temozolomide resistance mechanisms: unveiling the role of translesion DNA polymerase kappa in glioblastoma spheroids in vitro.

Temozolomide (TMZ) is the leading therapeutic agent for combating Glioblastoma Multiforme (GBM). Nonetheless, the persistence of chemotherapy-resistant GBM cells remains an ongoing challenge, attributed to various factors, including the translesion synthesis (TLS) mechanism. TLS enables tumor cells to endure genomic damage by utilizing specialized DNA polymerases to bypass DNA lesions.

Evaluation of Meibomian gland dysfunction using meibography in patients with xeroderma pigmentosum.

Purpose: To assess Meibomian gland dysfunction using meibography in patients with xeroderma pigmentosum and correlate with ocular surface changes.

Methods: This cross-sectional study evaluated patients with xeroderma pigmentosum. All patients underwent a comprehensive and standardized interview.

Genotoxicity of ultraviolet light and sunlight in the bacterium Caulobacter crescentus: Wavelength-dependence.

The ultraviolet (UV) component of sunlight can damage DNA. Although most solar UV is absorbed by the ozone layer, wavelengths > 300 nm (UVA and UVB bands) can reach the Earth's surface. It is essential to understand the genotoxic effects of UV light, particularly in natural environments.

Recombinant production of a highly efficient photolyase from Thermus thermophilus.

Ultraviolet (UV) radiation from sunlight can damage DNA, inducing mutagenesis and eventually leading to skin cancer. Topical sunscreens are used to avoid the effect of UV irradiation, but the topical application of DNA repair enzymes, such as photolyase, can provide active photoprotection by DNA recovery. Here we produced a recombinant Thermus thermophilus photolyase expressed in Escherichia coli, evaluated the kinetic parameters of bacterial growth and the kinetics and stability of the enzyme.

Polymerase iota plays a key role during translesion synthesis of UV-induced lesions in the absence of polymerase eta.

Xeroderma pigmentosum (XP) variant cells are deficient in the translesion synthesis (TLS) DNA polymerase Polη (eta). This protein contributes to DNA damage tolerance, bypassing unrepaired UV photoproducts and allowing S-phase progression with minimal delay. In the absence of Polη, backup polymerases perform TLS of UV lesions.

Mutational signatures and increased retrotransposon insertions in xeroderma pigmentosum variant skin tumors.

Xeroderma pigmentosum variant (XP-V) is an autosomal recessive disease with an increased risk of developing cutaneous neoplasms in sunlight-exposed regions. These cells are deficient in the translesion synthesis (TLS) DNA polymerase eta, responsible for bypassing different types of DNA lesions. From the exome sequencing of 11 skin tumors of a genetic XP-V patients' cluster, classical mutational signatures related to sunlight exposure, such as C>T transitions targeted to pyrimidine dimers, were identified.

Genomic mutation landscape of skin cancers from DNA repair-deficient xeroderma pigmentosum patients.

Xeroderma pigmentosum (XP) is a genetic disorder caused by mutations in genes of the Nucleotide Excision Repair (NER) pathway (groups A-G) or in Translesion Synthesis DNA polymerase η (V). XP is associated with an increased skin cancer risk, reaching, for some groups, several thousand-fold compared to the general population. Here, we analyze 38 skin cancer genomes from five XP groups.

Current state of knowledge of human DNA polymerase eta protein structure and disease-causing mutations.

POLη, encoded by the POLH gene, is a crucial protein for replicating damaged DNA and the most studied specialized translesion synthesis polymerases. Mutations in POLη are associated with cancer and the human syndrome xeroderma pigmentosum variant, which is characterized by extreme photosensitivity and an increased likelihood of developing skin cancers. The myriad of structural information about POLη is vast, covering dozens of different mutants, numerous crucial residues, domains, and posttranslational modifications that are essential for protein function within cells.

ATM Pathway Is Essential for HPV-Positive Human Cervical Cancer-Derived Cell Lines Viability and Proliferation.

Infection with some mucosal human papillomavirus (HPV) types is the etiological cause of cervical cancer and of a significant fraction of vaginal, vulvar, anal, penile, and head and neck carcinomas. DNA repair machinery is essential for both HPV replication and tumor cells survival suggesting that cellular DNA repair machinery may play a dual role in HPV biology and pathogenesis. Here, we silenced genes involved in DNA Repair pathways to identify genes that are essential for the survival of HPV-transformed cells.

DNA polymerase eta protects human cells against DNA damage induced by the tumor chemotherapeutic temozolomide.

Human DNA polymerases can bypass DNA lesions performing translesion synthesis (TLS), a mechanism of DNA damage tolerance. Tumor cells use this mechanism to survive lesions caused by specific chemotherapeutic agents, resulting in treatment relapse. Moreover, TLS polymerases are error-prone and, thus, can lead to mutagenesis, increasing the resistance potential of tumor cells.

Photorepair of Either CPD or 6-4PP DNA Lesions in Basal Keratinocytes Attenuates Ultraviolet-Induced Skin Effects in Nucleotide Excision Repair Deficient Mice.

Ultraviolet (UV) radiation is one of the most genotoxic, universal agents present in the environment. UVB (280-315 nm) radiation directly damages DNA, producing cyclobutane pyrimidine dimers (CPDs) and pyrimidine 6-4 pyrimidone photoproducts (6-4PPs). These photolesions interfere with essential cellular processes by blocking transcription and replication polymerases, and may induce skin inflammation, hyperplasia and cell death eventually contributing to skin aging, effects mediated mainly by keratinocytes.

Detection of Post-Replicative Gaps Accumulation and Repair in Human Cells Using the DNA Fiber Assay.

The DNA fiber assay is a simple and robust method for the analysis of replication fork dynamics, based on the immunodetection of nucleotide analogs that are incorporated during DNA synthesis in human cells. However, this technique has a limited resolution of a few thousand kilobases. Consequently, post-replicative single-stranded DNA (ssDNA) gaps as small as a few hundred bases are not detectable by the standard assay.

XPC and POLH/XPV Genes Mutated in a Genetic Cluster of Xeroderma Pigmentosum Patients in Northeast Brazil.

Xeroderma pigmentosum (XP) is a rare genetic condition in which exposure to sunlight leads to a high tumor incidence due to defective DNA repair machinery. Herein, we investigated seven patients clinically diagnosed with XP living in a small city, Montanhas (Rio Grande do Norte), in the Northeast region of Brazil. We performed high-throughput sequencing and, surprisingly, identified two different mutated genes.

Loss of Melanopsin (OPN4) Leads to a Faster Cell Cycle Progression and Growth in Murine Melanocytes.

Skin melanocytes harbor a complex photosensitive system comprised of opsins, which were shown, in recent years, to display light- and thermo-independent functions. Based on this premise, we investigated whether melanopsin, OPN4, displays such a role in normal melanocytes. In this study, we found that murine melanocytes displayed a faster proliferation rate compared to melanocytes.

Ru(II)/amino acid complexes inhibit the progression of breast cancer cells through multiple mechanism-induced apoptosis.

For some cancer subtypes, such as triple-negative breast cancer, there are no specific therapies, which leads to a poor prognosis associated with invasion and metastases. Ruthenium complexes have been developed to act in all steps of tumor growth and its progression. In this study, we investigated the effects of Ruthenium (II) complexes coupled to the amino acids methionine (RuMet) and tryptophan (RuTrp) on the induction of cell death, clonogenic survival ability, inhibition of angiogenesis, and migration of MDA-MB-231 cells (human triple-negative breast cancer).

Neurovascular dysfunction and neuroinflammation in a Cockayne syndrome mouse model.

Cockayne syndrome (CS) is a rare, autosomal genetic disorder characterized by premature aging-like features, such as cachectic dwarfism, retinal atrophy, and progressive neurodegeneration. The molecular defect in CS lies in genes associated with the transcription-coupled branch of the nucleotide excision DNA repair (NER) pathway, though it is not yet clear how DNA repair deficiency leads to the multiorgan dysfunction symptoms of CS. In this work, we used a mouse model of severe CS with complete loss of NER (), which recapitulates several CS-related phenotypes, resulting in premature death of these mice at approximately 20 weeks of age.

A therapeutic DNA vaccine and gemcitabine act synergistically to eradicate HPV-associated tumors in a preclinical model.

Although active immunotherapies are effective strategies to induce activation of CD8 T cells, advanced stage tumors require further improvements for efficient control. Concerning the burden of cancer-related to Human papillomavirus (HPV), particularly the high incidence and mortality of cervical cancer, our group developed an approach based on a DNA vaccine targeting the HPV-16 E7 oncoprotein (pgDE7h). This immunotherapy is capable of inducing an antitumour CD8 T cell response but show only partial control of tumors in more advanced growth stages.