DNA Repair (Amst)
September 2024
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.
View Article and Find Full Text PDFTemozolomide (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.
View Article and Find Full Text PDFMutat Res Genet Toxicol Environ Mutagen
March 2024
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.
View Article and Find Full Text PDFUltraviolet (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.
View Article and Find Full Text PDFXeroderma 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.
View Article and Find Full Text PDFMutat Res Rev Mutat Res
December 2022
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.
View Article and Find Full Text PDFInfection 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.
View Article and Find Full Text PDFXeroderma 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.
View Article and Find Full Text PDFSkin 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.
View Article and Find Full Text PDFOral Surg Oral Med Oral Pathol Oral Radiol
September 2021
Xeroderma pigmentosum (XP) is a rare inherited disease caused by deficiencies in DNA damage repair, which mainly results from the failure of nucleotide excision repair or defects in translesion DNA synthesis. The development of multiple malignancies is one of the most prominent features of this condition, which is clinically characterized by the occurrence of hyperpigmentation and lesions associated with sunlight exposure. Lip squamous cell carcinoma in patients with XP has rarely been reported, and information regarding the genetic analysis of these patients is limited.
View Article and Find Full Text PDFPurpose: To identify novel genes associated with intellectual disability (ID) in four unrelated families.
Methods: Here, through exome sequencing and international collaboration, we report eight individuals from four unrelated families of diverse geographic origin with biallelic loss-of-function variants in UBE4A.
Results: Eight evaluated individuals presented with syndromic intellectual disability and global developmental delay.
Glioblastoma is a severe type of brain tumor with a poor prognosis and few therapy options. Temozolomide (TMZ) is one of these options, however, with limited success, and failure is mainly due to tumor resistance. In this work, genome-wide CRISPR-Cas9 lentiviral screen libraries for gene knockout or activation were transduced in the human glioblastoma cell line, aiming to identify genes that modulate TMZ resistance.
View Article and Find Full Text PDFSemin Cell Dev Biol
June 2021
Human genetic syndromes deficient in nucleotide excision repair (NER), such as xeroderma pigmentosum and Cockayne syndrome, may present neurological abnormalities and premature aging symptoms. Unrepaired endogenously generated DNA damage that hampers transcription is a strong candidate that contributes to the development of these severe effects in neuronal tissue. Endogenous lesions include those generated due to byproducts of cellular metabolisms, such as reactive oxygen species.
View Article and Find Full Text PDFEnviron Int
December 2020
Biochim Biophys Acta Mol Cell Res
October 2020
Cutaneous melanocytes and melanoma cells express several opsins, of which melanopsin (OPN4) detects temperature and UVA radiation. To evaluate the interaction between OPN4 and UVA radiation, normal and malignant Opn4 and Opn4 melanocytes were exposed to three daily low doses (total 13.2 kJ/m) of UVA radiation.
View Article and Find Full Text PDFSunlight ultraviolet (UV) radiation constitutes an important environmental genotoxic agent that organisms are exposed to, as it can damage DNA directly, generating pyrimidine dimers, and indirectly, generating oxidized bases and single-strand breaks (SSBs). These lesions can lead to mutations, triggering skin and eye disorders, including carcinogenesis and photoaging. Stratospheric ozone layer depletion, particularly in the Antarctic continent, predicts an uncertain scenario of UV incidence on the Earth in the next decades.
View Article and Find Full Text PDFThe Xanthomonadaceae family comprises the genera Xanthomonas and Xylella, which include plant pathogenic species that affect economically important crops. The family also includes the plant growth-promoting bacteria Pseudomonas geniculata and Stenotrophomonas rhizophila, and some other species with biotechnological, medical, and environmental relevance. Previous work identified molecular signatures that helped to understand the evolutionary placement of this family within gamma-proteobacteria.
View Article and Find Full Text PDFPlants are continuously exposed to agents that can generate DNA lesions. Nucleotide Excision Repair (NER) is one of the repair pathways employed by plants to protect their genome, including from sunlight. The Xeroderma Pigmentosum type B (XPB) protein is a DNA helicase shown to be involved in NER and is also an essential subunitof the Transcription Factor IIH (TFIIH) complex.
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