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PubMed2004

Pedicle screw fixation with translaminar facet joint screws for the treatment of thoracolumbar fracture.

OBJECTIVE: To evaluate the efficacy of Cotrel-Dubeusset (CD) instrumentation combined with translaminar facet joint screw (TLS) in the treatment of thoracolumbar fracture. METHODS: A total of six L(2)-L(4) spines were used to establish unstable fracture model with three-dimensional range of motion (ROM) of the spines measured. Fixation with CD and fixation with CD combined with translaminar facet joint screw were achieved to compare their stability. Thirty cases of thoracolumbar fracture, in whom the anterior edge of vertebral body was compressed to 59% and the posterior edge compressed to 88%, were treated by pedicle screw fixation combined with TLS. Among them, 19 received posterolateral or anterior-posterior bone grafting. RESULTS: There was significant difference in ROM between the two techniques except that in extension. In Group CD+TLS, ROM was 5.38% lower, lateral bending 4.91% lower and axial rotation 11.85% lower than those in Group CD respectively. In the clinical group, the average anterior edge restored to 97% and posterior edge to 98%. The duration of follow-up was 5-24 months (mean, 10 months). The rate of correction loss on the anterior edge was 4.5%. Among the 19 cases of bone grafting, all of them achieved bony fusion (mean fusion time, 4.3 month) with a correction loss rate of 3.4%. CONCLUSIONS: In the treatment of thoracolumbar fracture, pedicle screw fixation combined with TLS can strengthen the stability of pedicle screws, especially anti-rotation stability and enhance fusion rate and reduce correction loss.

Adult↗

PubMed2026

Exploiting DNA damage tolerance for precision oncology.

Unresolved DNA lesions trigger replication stress, forcing cancer cells to hijack DNA damage tolerance (DDT) networks, specifically translesion synthesis (TLS) and template switching, to sustain replication. While DDT prevents lethal fork collapse, error-prone TLS drives mutagenesis, tumor evolution, chemoresistance and radioresistance. Proliferating cell nuclear antigen post-translational modifications dynamically govern pathway selection. Cancer cells exploit this plasticity, creating actionable vulnerabilities such as postreplicative single-stranded DNA gaps. Emerging inhibitors targeting TLS polymerases, upstream regulators such as ubiquitin-specific peptidase 1 (USP1), and critical protein-protein interactions offer unprecedented opportunities for precision oncology. By integrating DDT inhibition with biomarkers such as homologous recombination deficiency and tumor mutational burden, we can drive synthetic lethality, sensitize tumors to genotoxic agents, suppress treatment-induced mutagenesis, and potentially enhance responses to immunotherapy.

DDT↗

PubMed1999

Tumor lysis syndrome occurring after the administration of rituximab in lymphoproliferative disorders: high-grade non-Hodgkin's lymphoma and chronic lymphocytic leukemia.

Rituximab, an anti-CD20 antibody, has been recently approved for the treatment of low-grade or follicular non-Hodgkin's lymphoma (NHL). Because of its relatively benign side effect profile, it has been considered a nontoxic alternative to chemotherapy. Recently, however, tumor lysis syndrome (TLS) resulting from rituximab has been reported in a patient with chronic lymphocytic leukemia (CLL). We herein present two cases of rituximab-induced TLS. The first case occurred in a patient with high-grade NHL, while the second case occurred in a patient with CLL. We also present a summary of the literature regarding TLS induced by immunotherapies.

Adult↗

PubMed1998

Potential role of transoral laser surgery for larynx carcinoma.

BACKGROUND AND OBJECTIVE: The treatment of larynx carcinoma is not settled to date. This prospective study evaluates the potential role of transoral laser surgery (TLS) for larynx carcinoma in a large series of unselected patients from a single institution. MATERIALS AND METHODS: A total of 504 consecutive patients with previously untreated carcinoma of the larynx were seen from 1986-1994. Their treatment modalities and results were prospectively evaluated. RESULTS: TLS was used in 290 patients (58%), total laryngectomy in 130 (26%), conventional partial laryngectomies in 31 (6%), and radiotherapy in 34 (7%). Nineteen (4%) had no curative treatment. Uncorrected actuarial survival for all patients with glottic carcinoma stages I and II treated with laser surgery (n = 202) was 80.2%, cause specific survival 96.7%, and local control 85.8%. Uncorrected actuarial survival for all patients with supraglottic carcinoma stages I and II treated with laser surgery (n = 40) was 49.0%, cause specific survival 78.6%, and local control 87.3%. CONCLUSION: TLS was the most important single treatment modality in this large series of unselected patients. It is a safe and time- and cost-effective alternative to radiotherapy for early stage larynx carcinoma.

Carbon Dioxide↗

PubMed2003

Rasburicase (recombinant urate oxidase) for the management of hyperuricemia in patients with cancer: report of an international compassionate use study.

BACKGROUND: Hyperuricemia and tumor lysis syndrome (TLS) are serious complications that can occur during chemotherapy for hematologic malignancies, even if standard management procedures, including administration of allopurinol, are undertaken. Rasburicase, a recombinant urate oxidase that converts uric acid (UA) into the soluble compound allantoin, has been shown to control hyperuricemia faster and more reliably than allopurinol.(1) METHODS: A compassionate use trial, running from January 1999 to December 2001, provided access to rasburicase for patients in nine countries who were at risk for TLS during the initiation of chemotherapy. Of the 280 patients enrolled in the study, 278 received rasburicase and were included in the analysis. A total of 166 pediatric patients who had leukemia (approximately 74%), lymphoma (approximately 24%), or solid tumors (approximately 3%) were treated with rasburicase. One hundred twelve adults with either leukemia (68%) or lymphoma (30%) also were treated. Rasburicase (0.20 mg/kg) was administered intravenously once a day for 1 to 7 days, at the investigator's discretion. Two doses daily could be administered during the first 3 days. A response was defined as a reduction in UA level or maintenance of a UA level less than 7.5 mg/dL (or less than 6.5 mg/dL, for children age < 13 years). RESULTS: UA levels at 24-48 hours after administration of the last dose of rasburicase were available for 122 pediatric patients and 97 adult patients. The mean UA level in 29 hyperuricemic children decreased from 15.1 mg/dL to 0.4 mg/dL, whereas in 27 hyperuricemic adults, the mean level decreased from 14.2 mg/dL to 0.5 mg/dL. Prophylactic administration of rasburicase to prevent TLS during chemotherapy reduced UA levels from a mean of 4.4 mg/dL to 0.8 mg/dL in 93 nonhyperuricemic children and from 4.8 mg/dL to 0.4 mg/dL in 70 nonhyperuricemic adults (for all reductions in UA levels, P < 0.001). The response rate was 100%. Rasburicase was very well tolerated. Serious adverse events related to rasburicase were observed in one patient. CONCLUSIONS: The results of the current study confirm that rasburicase is safe and highly effective in the prevention and treatment of chemotherapy-induced hyperuricemia in both children and adults.

Adolescent↗

PubMed2002

Crystallographic dissection of the thermal motion of protein-sugar complex.

The crystal structure of turkey egg lysozyme (TEL) complexed with di-N-acetylchitobiose (NAG2) was refined at 1.19 A resolution by the full-matrix least-squares method with anisotropic temperature factors, and its thermal motion was evaluated by the TLS method. The average ESDs of atomic parameters of nonhydrogen atoms were 0.030 A for coordinates and 0.025 A(2) for anisotropic temperature factors. The active site cleft of TEL binds the alpha-anomer of NAG2 in a nonproductive binding mode with its pyranose rings parallel to a beta-sheet. The TEL structure was compared with the re-refined 1.12 A structure of native TEL. The RMS difference for equivalent Calpha atoms was 0.103 A and a relatively large difference was observed in the region of residues 104-125 rather than in the beta-sheet region where NAG2 was bound. In contrast, the temperature factor of the beta-sheet region was significantly decreased by the NAG2 binding. The TLS model that describes the rigid body motion in translation, libration, and screw motion was adopted for the evaluation of the molecular motion of TEL and NAG2, and the TLS parameters were determined by the least-squares fit to U(ij). The contribution of the external motion of TEL was estimated to be 55.8% of the observed temperature factor for the native structure and 45.9% for the NAG2 complex. The internal motion of TEL represented with atomic thermal ellipsoids was very similar between the native and complex structures except the NAG2 binding region. In the structure of NAG2, the rigid body motion dominates the thermal motion. The center of rotation of NAG2, 4.45A far from the center of gravity, is on the nitrogen atom of the acetylamino group that is hydrogen bonded to the main-chain peptide groups of Asn49 and Ala107. The rigid body motion of NAG2 indicates that the acetylamino group is most strongly bound to the active site, and the recognition of this group is a crucial step of the substrate binding.

Animals↗

PubMed2004

An atomic resolution structure for human fibroblast growth factor 1.

A 1.10-A atomic resolution X-ray structure of human fibroblast growth factor 1 (FGF-1), a member of the beta-trefoil superfold, has been determined. The beta-trefoil is one of 10 fundamental protein superfolds and is the only superfold to exhibit 3-fold structural symmetry (comprising 3 "trefoil" units). The quality of the diffraction data permits unambiguous assignment of Asn, Gln, and His rotamers, Pro ring pucker, as well as refinement of atomic anisotropic displacement parameters (ADPs). The FGF-1 structure exhibits numerous core-packing defects, detectable using a 1.0-A probe radius. In addition to contributing to the relatively low thermal stability of FGF-1, these defects may also permit domain motions within the structure. The availability of refined ADPs allows a translation/libration/screw (TLS) analysis of putative rigid body domains. The TLS analysis shows that beta-strands 6-12 together form a rigid body, and there is a clear demarcation in TLS motions between the adjacent carboxyl- and amino-termini. Although separate from beta-strands 6-12, the individual beta-strands 1-5 do not exhibit correlated motions; thus, this region appears to be comparatively flexible. The heparin-binding contacts of FGF-1 are located within beta-strands 6-12; conversely, a significant portion of the receptor-binding contacts are located within beta-strands 1-5. Thus, the observed rigid body motion in FGF-1 appears related to the ligand-binding functionalities.

Anisotropy↗

PubMed1999

Crystallographic evaluation of internal motion of human alpha-lactalbumin refined by full-matrix least-squares method.

The low temperature form of human alpha-lactalbumin (HAL) was crystallized from a 2H2O solution and its structure was refined to the R value of 0.119 at 1.15 A resolution by the full-matrix least-squares method. Average estimated standard deviations of atomic parameters for non-hydrogen atoms were 0.038 A for coordinates and 0.044 A2 for anisotropic temperature factors (Uij). The magnitude of equivalent isotropic temperature factors (Ueqv) was highly correlated with the distance from the molecular centroid and fitted to a quadratic equation as a function of atomic coordinates. The atomic thermal motion was rather isotropic in the core region and the anisotropy increased towards the molecular surface. The statistical analysis revealed the out-of-plane motion of main-chain oxygen atoms, indicating that peptide groups are in rotational vibration around a Calpha.Calpha axis. The TLS model, which describes the rigid-body motion in terms of translation, libration, and screw motions, was adopted for the evaluation of the molecular motion and the TLS parameters were determined by the least-squares fit to Uij. The reproduced Ueqvcal from the TLS parameters was in fair agreement with observed Ueqv, but differences were found in regions of residues, 5-22, 44-48, 70-75, and 121-123, where Ueqv was larger than Ueqvcal because of large local motions. To evaluate the internal motion of HAL, the contribution of the rigid-body motion was determined to be 42.4 % of Ueqv in magnitude, which was the highest estimation to satisfy the condition that the Uijint tensors of the internal motion have positive eigen values. The internal motion represented with atomic thermal ellipsoids clearly showed local motions different from those observed in chicken-type lysozymes which have a backbone structure very similar to HAL. The result indicates that the internal motion is closely related to biological function of proteins.

Calcium↗

PubMed1997

Turnip yellow mosaic virus RNA-dependent RNA polymerase: initiation of minus strand synthesis in vitro.

An RNA-dependent RNA polymerase (RdRp) activity was detergent-solubilized from the chloroplast membranes of Chinese cabbage leaves infected with turnip yellow mosaic virus (TYMV). The template-dependent, micrococcal nuclease-treated activity synthesized full-length minus strands from TYMV RNA and 3'-fragments as short as a 28-nucleotide-long RNA comprising the amino acid acceptor stem of the 3'-tRNA-like structure (TLS). Minus strands were shown to arise by de novo initiation with the insertion of GTP opposite the penultimate (C) residue of the 3'-terminal -CCA. The TYMV RdRp activity was template specific in that poly(A) RNA was not copied, and alfalfa mosaic virus (AIMV) RNA, which does not contain a 3'-TLS, was a very poor template. However, other viral RNAs with a 3'-TLS and in vitro transcripts of tRNAs were copied to varying degrees. Fully modified tRNAs were either inactive or poorly active templates, and AIMV 3'-RNA, even when provided with a 3'-terminal -ACCA, was not copied detectably. A potential role of the acceptor stem pseudoknot as a promoter element was assessed with mutations that drastically altered the structure and sequence of the pseudoknot, revealing only a twofold effect in decreasing template activity. The data show that RNAs with both a tRNA-like conformation and a -CCA 3'-terminus are potential templates for TYMV RdRp and suggest that promoter elements are not limited to the acceptor stem pseudoknot.

Base Sequence↗

PubMed1995

Prevention of tumor lysis syndrome using continuous veno-venous hemofiltration.

Tumor lysis syndrome (TLS) and renal failure remain significant causes of morbidity and mortality in children with newly diagnosed Burkitt's lymphoma and high white blood cell count acute lymphocytic leukemia (ALL) despite conventional management with aggressive hydration, alkalinization, allopurinol, and the slow introduction of chemotherapy. A subgroup of patients at very high risk for TLS and renal failure can be identified based on the level of serum lactate dehydrogenase (LDH) and urine output. We evaluated the prospective use of continuous veno-venous hemofiltration (CVVH), in addition to conventional management to prevent renal failure from tumor lysis, in three children with advanced abdominal Burkitt's lymphoma and in two children with high white blood cell count T-cell ALL who were at very high risk based on LDH and urine output. In this cohort of very high-risk patients, the LDH ratio (value at diagnosis/upper limit of normal) ranged from 0.88 to 10.3 and urine output from 0.13 to 4.7 ml/kg per hour. CVVH was begun at a mean time of 10.5 h before chemotherapy was initiated. Full-dose induction chemotherapy was begun within 24 h of diagnosis. After beginning CVVH, the uric acid levels decreased 46% prior to beginning chemotherapy and decreased to a mean of 4.2 mg/dl 24 h after chemotherapy was initiated. Four of the five patients had either no change or a drop in the serum creatinine. In patient one, blood urea nitrogen peaked at 58 mg/dl, and the creatinine at 4.7 mg/dl 6 days after beginning chemotherapy with a subsequent return to normal. Asymptomatic hypokalemia developed in all patients. After beginning chemotherapy, CVVH was continued for a mean of 85 h (range 70-91 h). No patient had complications secondary to CVVH. In summary, CVVH prevented renal failure secondary to TLS in 80% of these very high-risk patients. In the fifth patient, CVVH allowed full-dose chemotherapy to continue. The prospective use of CVVH could potentially decrease the morbidity and mortality associated with induction chemotherapy in very high-risk patients with a large tumor burden.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1984

Protective effect of bone marrow and spleen suspensions on radiation-induced leukemogenesis in C57BL/6 mice.

The present experiments are an attempt to precise the type and localization of the cells involved in the protective effect of hemopoietic suspensions against the radiation-induced thymic lymphosarcoma (TLS) of C57BL/6 mice. Inocula containing variable numbers of BM or spleen CFUs from 60-day-old and 360-day-old donors were tested. According to their origin, the suspensions differed with respect to the CFU replication rate, the CFU ability to differentiate towards the T lineage and the content of the suspensions in thymic precursors. Two levels of inhibition were observed: BM suspensions from 60-day-old donors containing 1,500 CFUs had the best protective effect: 14.5% of TLS; 1,500 CFUs from 360-day-old donors were slightly but not significantly less efficient (28.5%). The second level of inhibition (36-46% of TLS) was obtained with all the following inocula: a) 1,200 and 300 spleen CFUs or 300 and 95 BM CFUs from 60-day-old donors, b) 1,500 spleen CFUs from aged donors. Seventy-six spleen CFUs from 60-day-old donors, 120 BM or 175 spleen CFUs from aged donors had no effect. These results suggest that in addition to the high replication rate of the BM CFUs as compared with spleen CFUs, cells endowed with an optimal protective effect are present in BM suspensions and are either absent or present in very small amount in spleen suspensions. These cells which induce an early repopulation of the thymus might correspond to thymic precursors.

Animals↗

PubMed1992

Differential diagnostic patterns of lung neuroendocrine tumours. A clinico-pathological and immunohistochemical study of 122 cases.

A series of 3 tumourlets (TLs), 81 typical carcinoids (TCs), 14 atypical carcinoids (ACs) (well-differentiated neuroendocrine carcinomas, WDNCs) and 24 small cell-intermediate cell carcinomas (SCC-ICCs) of the lung were studied. Histopathological features were correlated with amine and peptide hormone immunoreactivity and with clinical data. All types of tumours expressed general neuroendocrine (NE) markers: Grimelius positivity and chromogranins were detected more frequently in well-differentiated (TLs, TCs) than in less well differentiated tumours [ACs (WDNCs) and SCC-ICCs] whereas neuron specific enolase (NSE) was prominent in the latter tumours. TLs and peripheral TCs were benign, often showing a paraganglioid pattern and frequently expressing gastrin-releasing peptide (GRP), which is present in the peripheral airways of normal lung. Central TCs were associated with lymph node metastases in 8.5% of the cases, frequently had a trabecular architecture, often associated with human milk fat globule 2 (HMFG2)-positive acinar and rosette-like structures, and were mainly immunostained for the alpha-subunit of human chorionic gonadotrophin (alpha-hCG) and serotonin. ACs (WDNCs) were associated with intrathoracic and/or extrathoracic metastases in 57.1% of the cases with a mortality rate of 35.7%. Their histological and cytological features were intermediate between those of TCs and SCC-ICCs. ACs (WDNCs) expressed serotonin and alpha-hCG less frequently than TCs. All SCC-ICCs were surgically treated and displayed a mortality rate of 91.6% with a mean survival of 10.2 months after operation. These tumours were characterized by high expression of HMFG2 and NSE, while the expression of both orthotopic (serotonin, GRP) and ectopic (ACTH) specific NE substances was very low. Since all TCs (either central or peripheral) had a favourable outcome, while about 36% of ACs (WDNCs) were fatal, the latter seem more appropriately designated "well-differentiated NE carcinomas". The differential diagnosis between different NE tumours of the lung is important and is mainly based on morphology. Both panendocrine and specific immunohistochemical markers are helpful in distinguishing the less aggressive, mostly benign varieties from the more malignant varieties.

Adult↗

PubMed1998

Estimation of evoked potentials using total least squares prony technique.

The authors investigate the applicability of Prony modelling to the estimation of evoked potentials. Four types of total least squares (TLS) model are considered and their optimal parameters are defined based on ten visual averaged EPs. Simulations with various signal and noise characteristics show that the TLS-Prony estimation is superior to averaging for two of the models, namely the unconstrained and the stable models. Application of the TLS-Prony estimator as a post-processor to moderate averaging allows a reduction in the number of responses averaged, or equivalently of recording time, by a factor of two.

Evoked Potentials, Visual↗

PubMed2004

Tumor lysis syndrome following docetaxel therapy for extensive metastatic prostate cancer.

Tumor Lysis Syndrome (TLS) is characterized by biochemical changes due to rapid tumor lysis of malignant cells, usually after chemotherapy. Typically it is seen in patients with hematologic malignancies sensitive to chemotherapy within days of receiving chemotherapy. Recently Baeksgaard and Sorensen reviewed the small number of cases of TLS after treatment of nonhematologic malignancies reported between 1977 and 2002. After careful review of the literature, I describe what appears to be to the first reported case of TLS associated with chemotherapeutic treatment of metastatic prostate cancer.

Adenocarcinoma↗

PubMed2003

Pan-European multicentre economic evaluation of recombinant urate oxidase (rasburicase) in prevention and treatment of hyperuricaemia and tumour lysis syndrome in haematological cancer patients.

GOALS: Hyperuricaemia (HU) and tumour lysis syndrome (TLS) are complications of acute myeloid/lymphoid leukaemia (AML/ALL) and non-Hodgkin lymphoma (NHL) leading to increased morbidity and mortality. The objective was to assess incremental cost-effectiveness ratios (ICER) of preventing/treating HU and TLS with recombinant urate oxidase, rasburicase (Fasturtec/Elitek). PATIENTS AND METHODS: Incidence and costs of HU and TLS were based on a multi-country chart review. Life expectancy at the time of diagnosis was based on published survival rates and age at diagnosis. Reductions of HU/TLS following treatment with rasburicase were based on clinical trial data. RESULTS: Prevention with rasburicase appears highly cost-effective in children (ICER between Eur 425 and Eur 3054 per life-year saved, LYS). In adults, prevention is more cost-effective in NHL and ALL (maximum ICER of Eur 41383 and Eur 32126 per LYS). Treatment of established HU/TLS with rasburicase is cost-saving in children and highly cost-effective in adults. The results are robust in children. In adults, the prevention strategy appears sensitive to the risk of HU/TLS. CONCLUSIONS: In conclusion, rasburicase, in addition to the demonstrated clinical benefit, is an economically attractive new option in the treatment of HU, both in adults and children. In prevention the drug has an attractive economic profile in children, and is cost-effective in adults with ALL and NHL.

Adult↗

PubMed2026

Pan-cancer single-cell atlas of immunotherapy response identifies ZNF385A as a regulator of immune evasion in small cell lung cancer.

Although immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape of solid tumors, response rates in patients with small cell lung cancer (SCLC) remain limited, and acquired resistance is highly prevalent. The underlying mechanisms of this immunotherapy resistance remain to be fully elucidated. Clinically, SCLC typically manifests as an "immune-cold" tumor, characterized by a low abundance of CD8+ T cell infiltration and the rare formation of tertiary lymphoid structures (TLS). While DNA damage repair (DDR) is closely linked to innate immune responses, how DDR networks orchestrate the SCLC immune microenvironment remains obscure. In this study, we integrated single-cell transcriptomic data (comprising 344,447 high-quality cells) from six cancer types (BCC, CRC, HCC, HNSCC, iCCA, and SCLC). Our comparative analysis revealed a fundamental depletion of TLS-associated cellular subpopulations (e.g., CXCL13+ CD8+ T cells, HLA-DRB5+ B cells, and CXCL9+ dendritic cells) in SCLC, which was significantly correlated with aberrant DDR activity. Through high-dimensional weighted gene co-expression network analysis (hdWGCNA), we identified ZNF385A as the core hub gene within the DDR-associated module. ZNF385A is highly expressed in SCLC and is associated with poorer prognosis. In vitro, ZNF385A depletion suppressed SCLC cell proliferation and induced apoptosis, accompanied by R-loop accumulation and activation of cGAS-STING signaling, indicating a potential link between ZNF385A, genomic stability and tumor-intrinsic innate immune signaling. Collectively, these findings identify ZNF385A as a potential regulator associated with TLS deficiency and immune evasion in SCLC.

Immunotherapy resistance↗

PubMed2005

Low cytotoxicity of ecteinascidin 743 in yeast lacking the major endonucleolytic enzymes of base and nucleotide excision repair pathways.

Ecteinascidin 743 (ET-743) is a promising antitumoral drug for the treatment of soft tissues sarcomas, becoming a good candidate for clinical trials. However, the molecular mechanism of how ET-743 induces cells death is poorly understood. The chemical structure of ET-743 suggests that it can form cytotoxic cross-links with proteins and DNA. Experiments with Escherichia coli and mammalian cells indicate that the nucleotide excision repair (NER) pathway promotes ET-743 cytotoxicity. We therefore analyzed cytotoxicity and tolerance to ET-743 in the yeast Saccharomyces cerevisiae, defective for NER and/or base excision repair (BER), either in single mutants or in combination with mutant alleles of genes encoding proteins involved in DNA translesion synthesis (TLS) and homologous recombination (HR). Treatment of haploid and diploid S. cerevisiae strains with ET-743 led to induced mutagenesis, mitotic gene conversion, and crossing-over. The results indicated that yeast strains lacking endonucleases of the NER and BER pathways are especially resistant for ET-743. The mutagenesis data points to a weak mutagenic activity of ET-743 in both WT and strains lacking BER/NER endonuclease, and that a mutant blocked in both BER and TLS totally lacks induced mutagenesis. The diploid strain shows an increase in the frequencies of crossing-over and mitotic recombination. These data lead us to propose a model for ET-743 action in eukaryotic cells, where the presence of BER and NER endonucleases results in cell death. However, ET-743 damage can be tolerated in BER and/or NER mutants by TLS (error-prone) or in combination with HR (error-free).

Antineoplastic Agents↗

PubMed2003

Xeroderma pigmentosum variant and error-prone DNA polymerases.

Replicative DNA synthesis is a faithful event which requires undamaged DNA and high fidelity DNA polymerases. If unrepaired damage remains in the template DNA during replication, specialised low fidelity DNA polymerases synthesises DNA past lesions (translesion synthesis, TLS). Current evidence suggests that the polymerase switch from replicative to translesion polymerases might be mediated by post-translational modifications involving ubiquitination processes. One of these TLS polymerases, polymerase eta carries out TLS past UV photoproducts and is deficient in the variant form of xeroderma pigmentosum (XP-V). The dramatic proneness to skin cancer of XP-V individuals highlights the importance of this DNA polymerase in cancer avoidance. The UV hypermutability of XP-V cells suggests that, in the absence of a functional poleta, UV-induced lesions are bypassed by inaccurate DNA polymerase(s) which remain to be identified.

Animals↗