Bioinformatics and expression analysis of the Xeroderma Pigmentosum complementation group C (XPC) of Trypanosoma evansi in Trypanosoma cruzi cells

Nucleotide excision repair (NER) acts repairing damages in DNA, such as lesions caused by cisplatin. Xeroderma Pigmentosum complementation group C (XPC) protein is involved in recognition of global genome DNA damages during NER (GG-NER) and it has been studied in different organisms due to its importance in other cellular processes. In this work, we studied NER proteins in Trypanosoma cruzi and Trypanosoma evansi, parasites of humans and animals respectively. We performed three-dimensional models of XPC proteins from T. cruzi and T. evansi and observed few structural differences between these proteins. In our tests, insertion of XPC gene from T. evansi (TevXPC) in T. cruzi resulted in slower cell growth under normal conditions. After cisplatin treatment, T. cruzi overexpressing its own XPC gene (TcXPC) was able to recover cell division rates faster than T. cruzi expressing TevXPC gene. Based on these tests, it is suggested that TevXPC (being an exogenous protein in T. cruzi) interferes negatively in cellular processes where TcXPC (the endogenous protein) is involved. This probably occurred due interaction of TevXPC with some endogenous molecules or proteins from T.cruzi but incapacity of interaction with others. This reinforces the importance of correctly XPC functioning within the cell.

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. Six patients carry a novel homozygote mutation in the POLH/XPV gene, c.672_673insT (p.Leu225Serfs*33), while one patient carries a homozygote mutation in the XPC gene, c.2251-1G>C. This latter mutation was previously described in Southeastern Africa (Comoro Island and Mozambique), Pakistan, and in a high incidence in Brazil. The XP-C patient had the first symptoms before the first year of life with aggressive ophthalmologic tumor progression and a melanoma onset at 7 years of age. The XP-V patients presented a milder phenotype with later onset of the disorder (mean age of 16 years old), and one of the six XP-V patients developed melanoma at 72 years. The photoprotection is minimal among them, mainly for the XP-V patients. The differences in the disease severity between XP-C (more aggressive) and XP-V (milder) patients are obvious and point to the major role of photoprotection in the XPs. We estimate that the incidence of XP patients at Montanhas can be higher, but with no diagnosis, due to poor health assistance. Patients still suffer from the stigmatization of the condition, impairing diagnosis, education for sun protection, and medical care.

Xeroderma Pigmentosum: Clinical and Genetic Features and Therapeutic Approaches

Xeroderma pigmentosum is rare genetic disorder characterized by increased skin sensitivity to damaging ultraviolet (UV) light. First symptoms manifest at early age in most cases (up to 75%). Chronic damage due to sun exposure is common, it has different stages of changes and risk of further development of malignant tumors that depends on the gene involved. Additionally to skin manifestations there are various neurological disorders such as progressive cognitive dysfunctions, sensorineural hearing loss, ataxia, pyramid and extrapyramidal disorders, areflexia. Treatment of patients with xeroderma pigmentosum is mostly symptomatic and preventive (protection against UV). Nowadays targeted medications for DNA repair and increasing cells resistance to UV light, thus preventing the oncological diseases, are under development.

Increased Risk of Internal Tumors in DNA Repair-Deficient Xeroderma Pigmentosum Patients: Analysis of Four International Cohorts

Background Xeroderma pigmentosum (XP) is a rare, autosomal, recessive DNA repair-deficiency disorder with a frequency of 1-3 per million livebirths in Europe and USA but with higher frequencies in isolated islands or in countries with a high level of consanguinity. XP is characterized by high incidence of skin cancers on sun-exposed sites. Recent improvement in life expectancy of XP patients suggests an increased risk of frequently aggressive and lethal internal tumors. Our purpose was to quantify relative risks of internal tumor development for XP patients by tumor type, XP-subtype, patients’ ages and ethnicity through comparison with the US general population. Methods We analyzed four independent international well-characterized XP cohorts (from USA, UK, France and Brazil) with a total of 434 patients, where 11.3% developed internal tumors and compared them to the American general population. We also compiled, through PubMed/Medline, a dataset of 89 internal tumors in XP patients published between 1958 and 2020. Results In the combined 4-XP cohort, relative risk of internal tumors was 34 (95% confidence interval (CI) 25-47) times higher than in the general population (p-value=1.0E-47) and tumor arose 50 years earlier. The XP-C group was at the highest risk for the 0-20 years old-patients (OR=665; 95% CI 368-1200; p-value=4.3E-30). The highest risks were observed for tumors of central nervous system (OR=331; 95% CI 171-641; p-value=2.4E-20), hematological malignancies (OR=120; 95% CI 77-186; p-value=3.7E-36), thyroid (OR=74; 95% CI 31-179; p-value=1.2E-8) and gynecological tumors (OR=91; 95% CI 42-193; p-value=3.5E-12). The type of mutation on the XPC gene is associated with different classes of internal tumors. The majority of French XP-C patients (80%) are originated from North Africa and carried the XPC delTG founder mutation specific from the South Mediterranean area. The OR is extremely high for young (0-20 years) patients with more than 1,300-fold increase for the French XPs carrying the founder mutation. Conclusion Because the age of XP population is increasing due to better sun-protection and knowledge of the disease, these results are of particular importance for the physicians to help in early prevention and detection of internal tumors in their XP patients. Few preventive blood analyses or simple medical imaging may help to better detect early cancer appearance in this population.

Unresectable and chemoresistant conjunctival squamous cell carcinoma on xeroderma pigmentosum treated by salvage radiation therapy: A case report and a review of the literature

Radiotherapy, by its mechanism, has always been suspected to be contra-indicated in patients with xeroderma pigmentosum, depriving them of this very effective modality in the treatment of their cancers. As these suspicions have still not been confirmed, the place of radiotherapy should be reconsidered, while applying precautionary principles.

Effects of 5′,8′-Cyclo-2′-Deoxypurines on the Base ExcisionRepair of Clustered DNA Lesions in Nuclear Extracts of the XPC Cell Line

Clustered DNA lesions (CDL) containing 5′,8-cyclo-2′-deoxypurines (cdPus) are an example of extensive abnormalities occurring in the DNA helix and may impede cellular repair processes. The changes in the efficiency of nuclear base excision repair (BER) were investigated using (a) two cell lines, one of the normal skin fibroblasts as a reference (BJ) and the second from Xeroderma pigmentosum patients’ skin (XPC), and (b) synthetic oligonucleotides with single- and double-stranded CDL (containing 5′,8-cyclo-2′-deoxyadenosine (cdA) and the abasic (AP) site at various distances between lesions). The nuclear BER has been observed and the effect of both cdA isomers (5′R and 5′S) presence in the DNA was tested. CdPus affected the repair of the second lesion within the CDL. The BER system more efficiently processed damage in the vicinity of the ScdA isomer and changes located in the 3′-end direction for dsCDL and in the 5′-end direction for ssCDL. The presented study is the very first investigation of the repair processes of the CDL containing cdPu considering cells derived from a Xeroderma pigmentosum patient.