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PubMed2004

Ubiquitination of PCNA and the polymerase switch in human cells.

Replicative DNA polymerases are blocked by damage in the template DNA. To get past this damage, the cell employs specialized translesion synthesis (TLS) polymerases, which have reduced stringency and are able to bypass different lesions. For example, DNA polymerase eta (poleta) is able to carry out TLS past UV-induced cyclobutane pyrimidine dimers. How does the cell bring about the switch from replicative to TLS polymerase? We have shown that, in human cells, when the replication machinery is blocked at DNA damage, PCNA, the sliding clamp required for DNA replication, is mono-ubiquitinated and that this modified form of PCNA has increased affinity for poleta. This provides a mechanism for the polymerase switch. In this Extra-View, we discuss the possible signals that might trigger ubiquitination of PCNA, whether PCNA becomes de-ubiquitinated after TLS has been accomplished and the role of the hREV1 protein in TLS. We point out some apparent differences between mechanisms in Saccharomyces cerevisiae and human cells.

DNA Replication↗

PubMed1994

Characterization of the pharmacodynamics of several antiepileptic drugs in a direct cortical stimulation model of anticonvulsant effect in the rat.

In this investigation a newly developed direct cortical stimulation technique was evaluated for measurement of anticonvulsant efficacy in rats. The kinetics of drug action for carbamazepine, phenytoin, valproate, phenobarbital, ethosuximide and oxazepam were studied in conjunction with their pharmacokinetics. Motor cortex stimulation with a ramp-shaped pulse train allowed successive determination of a threshold for localized seizure activity (TLS) and for generalized seizure activity (TGS). For each drug the time course of effect was followed in individual animals. Differential effects on the pharmacodynamic parameters were seen. Phenytoin and carbamazepine clearly elevated the TGS. However, phenytoin did not affect TLS and carbamazepine only marginally. Valproate increased both TLS and TGS to the same extent. Phenobarbital and oxazepam elevated both thresholds, but the effect on TGS was more pronounced. Ethosuximide had little effect on both thresholds. Comparison with other animal models suggested that elevation of TLS reflects an effect on seizure initiation, whereas elevation of TGS above TLS reflects an effect on seizure propagation. All drugs exhibited a nonlinear relationship between plasma concentration and anticonvulsant efficacy, without ceiling of anticonvulsant intensity at the highest concentrations. The effective concentration range of most compounds coincided with the "therapeutic" range in humans. The direct cortical stimulation technique is useful for preclinical monitoring of anticonvulsant efficacy with most antiepileptic drugs because it allows detection of both qualitative and quantitative differences. In addition the model is particularly useful for time course studies.

Animals↗

PubMedDate not supplied

Acute tumor lysis syndrome: assessment and nursing implications.

Acute tumor lysis syndrome (TLS) is a metabolic complication that occurs in some patients with cancer and frequently is triggered by chemotherapy. TLS results from a rapid destruction of a large number of tumor cells, which causes several potentially fatal biochemical changes. If not identified and treated quickly, TLS can result in acute renal failure. TLS often is associated with tumors that have high growth fractions. Typically, these tumors are very sensitive to the effects of chemotherapeutic agents. Fortunately, this complication can be prevented with appropriate medical and nursing management of patients at high risk. This article reviews the pathogenesis and medical treatment of TLS and identifies nursing implications for oncology nursing practice.

Humans↗

PubMed1997

Enhancement of thymic lymphocyte proliferation by the culture supernatant of thymus epithelial cells stimulated by prolactin.

Culture supernatant of thymus epithelial cells (TECs) stimulated by prolactin (PRL) enhanced markedly DNA synthetic activity of thymic lymphocytes (TLs) as compared with the hormone-non-stimulated TECs. The supernatant, which was treated with anti-insulin-like growth factor-I (IGF-I) monoclonal antibody (MAb) (binding specifically to C region of IGF-I) has still the capacity of enhancing remarkably TL-proliferation. However, further treatment by ultrafiltration of the MAb-treated supernatant, removing the immune complex (IGF-I and anti-IGF-I MAb) from the supernatant, suppressed significantly the enhanced proliferation of TLs. It is assumed that PRL, like growth hormone (GH), promotes the release of IGF-I from TECs which induces a marked TL-proliferation. Moreover, it seems that the active site for inducing the proliferation is a region different from C, possibly the A or the B regions. TLs, present at different maturation steps, were separated into three subsets by discontinuous density gradient centrifugation and then treated with the supernatant of PRL-stimulated TECs. The least dense subset containing precursor T-cells and the most immature TLs showed the highest proliferative response to the supernatant in the comparison with other subsets and whole TLs. It is possible that the target cells to one of TL-proliferation-inducing factors (PIFs), namely IGF-I, in the supernatant exist in a greater concentration in the most immature step of TL population.

Animals↗

PubMed1997

Determination of anticonvulsant effects on seizure thresholds using ramp generated cortical stimulation in conscious rats.

The purpose of this investigation was to evaluate the new technique of direct cortical stimulation in conscious rats, using ramp generated pulse trains. In rats with electrodes permanently implanted in the frontoparietal cortex, twice daily stimulation for a fortnight, with ramp shaped trains of 2 msec duration, frequency 50 Hz, ramp time 200 sec and incrementing 5 microA per 0.1 sec yielded reproducible convulsive thresholds which could be repeated at short intervals over a period of time. Two different pharmacodynamic parameters viz Threshold for Localized Seizures (TLS) and Threshold for Generalised Seizure (TGS) could be distinguished. TLS is defined as the current (microA) required to elicit forelimb clonus or minimal restricted seizure activity and at the 14th session was found to be 650 +/- 91 microA (n = 14). TGS is defined as the current (microA), at which forceful clonic jerks and vigorous clonic activity without the tonic component occurred, and at the 14th session was found to be 1059 +/- 171 microA (n = 23). The effect of (doses, mg/kg, ip),phenytoin (PHY)10, carbamazepine (CBZ) 10 and 20; sodium valproate (SV) 300 and ethosuximide (ESM) 200 were studied on the TLS and TGS (n = 6). PHY, CBZ and SV significantly elevated both TLS and TGS, whereas ESM was ineffective. PHY and CBZ elevated thresholds within 0.5 hr and continued for 5 to 6 hr. For SV, significant elevation of TLS and TGS commenced at 5 to 10 min and lasted about 4 hr. Comparison of these results with conventional methods, suggests that this model provides a new dimension to profiling anticonvulsant compounds, with better extrapolation to clinical situations.

Animals↗

PubMed1998

Full-matrix least-squares refinement of lysozymes and analysis of anisotropic thermal motion.

Crystal structures of turkey egg lysozyme (TEL) and human lysozyme (HL) were refined by full-matrix least-squares method using anisotropic temperature factors. The refinement converged at the conventional R-values of 0.104 (TEL) and 0.115 (HL) for reflections with Fo > 0 to the resolution of 1.12 A and 1.15 A, respectively. The estimated r.m.s. coordinate errors for protein atoms were 0.031 A (TEL) and 0.034 A (HL). The introduction of anisotropic temperature factors markedly reduced the R-value but did not significantly affect the main chain coordinates. The degree of anisotropy of atomic thermal motion has strong positive correlation with the square of distance from the molecular centroid. The ratio of the radial component of thermal ellipsoid to the r.m.s. magnitude of three principal components has negative correlation with the distance from the molecular centroid, suggesting the domination of libration rather than breathing motion. The TLS model was applied to elucidate the characteristics of the rigid-body motion. The TLS tensors were determined by the least-squares fit to observed temperature factors. The profile of the magnitude of reproduced temperature factors by the TLS method well fitted to that of observed B(eqv). However, considerable disagreement was observed in the shape and orientation of thermal ellipsoid for atoms with large temperature factors, indicating the large contribution of local motion. The upper estimate of the external motion, 67% (TEL) and 61% (HL) of B(eqv), was deduced from the plot of the magnitude of TLS tensors determined for main chain atoms which were grouped into shells according to the distance from the center of libration. In the external motion, the translational portion is predominant and the contribution of libration and screw motion is relatively small. The internal motion, estimated by subtracting the upper estimate of the external motion from the observed temperature factor, is very similar between TEL and HL in spite of the difference in 54 of 130 amino acid residues and in crystal packing, being suggested to reflect the intrinsic internal motion of chicken-type lysozymes.

Animals↗

PubMed1993

Adoptive chemoimmunotherapy using ex vivo activated memory T-cells and cyclophosphamide: tumor lysis syndrome of a metastatic soft tissue sarcoma.

Adoptively transferred immune cells in combination with chemotherapeutic agents form the basis for adoptive chemoimmunotherapy (ACIT) of neoplastic disease. Autolymphocytes (ALT-cells) are ex vivo activated peripheral blood lymphocytes (PBL) from tumor-bearing hosts (TBH) that consist primarily of tumor-specific CD45RO+ (memory) T-cells. These ALT-cells combined with cimetidine (CIM) as autolymphocyte therapy (ALT), have previously been demonstrated to be a safe and active form of outpatient adoptive immunotherapy (AIT) in human TBH with metastatic renal cell cancer (RCC). We have previously described an effective ACIT protocol using ALT and cyclophosphamide (CY) for patients with relapsed and refractory non-RCC solid tumors. We now report a case of a patient with a metastatic gastric leiomyosarcoma to the liver, who developed a clinical picture consistent with a tumor-lysis syndrome (TLS), following salvage therapy for his tumor with ACIT using ALT and CY. TLS is a well-known complication resulting from the treatment of rapidly proliferating hematopoietic tumors such as Burkitt's lymphoma and acute lymphocytic leukemia. TLS has also been rarely described in chronic lymphocytic leukemia, as well as certain solid tumors such as breast cancer, small cell lung cancer, and medulloblastoma. However, there have been no previous reports of TLS occurring either secondary to immunotherapy or in sarcomas. The nature of these unusual findings is discussed.

Aged↗

PubMed2004

CO2 laser surgery: a larynx preservation alternative for selected hypopharyngeal carcinomas.

BACKGROUND: Transoral CO2 laser surgery (TLS) has demonstrated good oncologic results and low morbidity in the treatment of selected laryngeal carcinomas, but experience in hypopharyngeal carcinomas (HC) is limited. The aim of this study was to evaluate the usefulness of TLS in the treatment of selected HC. METHODS: Twenty-eight patients with HC were treated with TLS and neck dissection. Tumors with preoperative invasion of thyroid cartilage at CT, deep growth into the cervical space or tongue base, and tumors crossing the posterior midline or involving the cervical esophagus were excluded. Postoperative radiation to the neck was administered when more than one lymph node was involved, when the metastasis diameter was greater than 2 cm, or when extranodal spread was found at the pathologic study. RESULTS: The sample included two T1, 16 T2, nine T3, and one T4 tumors. Stage classification was: II, 21.4%; III, 28.6%; and IV, 50%. Four-year overall and disease-specific survival rates were 43.4% and 59.4%, respectively, with 78.5% function preservation. Nine patients (32.1%) did not need a nasogastric feeding tube. The mean duration of the feeding tube in the remaining patients was 15.27 +/- 27.3 days. We had two postoperative bleeding episodes that required endoscopic coagulation and three postoperative pneumonias caused by aspiration. CONCLUSIONS: TLS is an alternative for the treatment of selected HC associated with a high larynx preservation rate.

Adult↗

PubMed2001

Hand-assisted laparoscopic surgery (HALS) for live donor nephrectomy is more time- and cost-effective than standard laparoscopic nephrectomy.

BACKGROUND: Hand-assisted laparoscopy (HALS) was introduced to increase the safety of living donor nephrectomies. Herein we evaluate the first HALS living donor nephrectomies performed at our center. METHODS: Traditional laparoscopic nephrectomies (TLS) (n = 11) and HALS nephrectomies (n = 11) were included in the study. One patient from the TLS group was excluded because the operation was converted to open nephrectomy. We compared the operating times (OT) and warm ischemia times (WIT) for the two procedures and calculated the operating costs. RESULTS: Mean OT was 270 min in the TLS group and 197 min in the HALS group; thus, there was, a significant reduction of 27% with HALS. WIT was 297 sec for the TLS group and 214 sec for the HALS group, for a reduction of 28%. Costs were also lowered for HALS. CONCLUSION: In addition to shortening both OT and WIT, HALS enhances the safety margin of the procedure, especially during trocar placement. It is further helpful in preventing torsion of the kidney and controlling potential bleedings, as well as during vascular stapling and kidney removal.

Adult↗

PubMed2001

Spontaneous acute tumour lysis syndrome in patients with metastatic germ cell tumours. Report of two cases.

Acute tumour lysis syndrome (TLS), a condition resulting from rapid destruction of tumour cells with massive release of cellular breakdown products, has been described following the treatment of various malignancies. However, spontaneous TLS has been described only rarely. Germ cell tumours (GCT) have a rapid cell turnover and often present with bulky metastatic disease. We report two cases of patients with metastatic GCT presenting with acute renal failure attributable to spontaneous TLS. All clinical and biochemical features of the syndrome were present. Both patients were treated with haemodialysis and intravenous administration of single-agent etoposide between dialysis sessions, resulting in recovery of renal function and marked decrease in tumour bulk within the first week after presentation. These cases are the first reported instances of spontaneous TLS in poor-risk metastatic GCT. Successful treatment with dialysis and chemotherapy is possible, and prophylactic vigorous hydration and allopurinol may be warranted in this setting.

Acute Kidney Injury↗

PubMed1998

The role of supplemental translaminar screws in anterior lumbar interbody fixation: a biomechanical study.

The immediate stabilization provided by anterior interbody cage fixation is often questioned. Therefore, the role of supplementary posterior fixation, particularly minimally invasive techniques such as translaminar screws, is relevant. The purpose of this biomechanical study was to determine the immediate three-dimensional flexibility of the lumbar spine, using six human cadaveric functional spinal units, in four different conditions: (1) intact, (2) fixed with translaminar screws (TLS), (3) instrumented with anterior interbody cage insertion with the BAK system and (4) instrumented with BAK cage with additional TLS fixation. Flexibility was determined in each testing condition by measuring the vertebral motions under applied pure moments (i.e. flexion-extension, bilateral axial rotation, bilateral lateral bending) in an unconstrained manner. Anterior fixation with the BAK alone provided significant stability in flexion and lateral bending. Additional posterior TLS significantly reduced the motion in extension and axial rotation. TLS fixation alone resulted in smaller rotations than BAK fixation in all loading directions. Based on these results, it seems that interbody cage fixation with the BAK system stabilizes the spine in some, but not all, loading directions. The problematic loading directions of extension and axial rotation can be substantially stabilized by using translaminar screw fixation. However, one should emphasize that the degree of stability needed to achieve solid fusion is not known.

Biomechanical Phenomena↗

PubMed2006

Assessment of respondent driven sampling for recruiting female sex workers in two Vietnamese cities: reaching the unseen sex worker.

Respondent driven sampling (RDS) is a relatively new method to sample hard-to-reach populations. Until this study, female sex workers (FSWs) in Vietnam were sampled using a variety of methods, including time location sampling (TLS), which may not access the more hidden types of FSWs. This paper presents an analysis from an HIV biological and behavioral surveillance survey to assess the feasibility and effectiveness of RDS to sample FSWs, to determine if RDS can reach otherwise inaccessible FSWs in Vietnam and to compare RDS findings of HIV risk factors with a theoretical TLS. Through face-to-face interviews with FSWs in Ho Chi Minh City (HCMC) and Hai Phong (HP), data were collected about the venues where they most often solicit their clients. These data were used to create three variables to assess whether FSWs solicit their clients in locations that are visible, semi-visible and non-visible. For this analysis, the visible group simulates a sample captured using TLS. Survey results in HIV prevalence and related risk factors and service utilization, adjusted for sampling methodology, were compared across each of the three FSW visibility groups to assess potential bias in TLS relative to RDS. The number of self-reported visible FSWs (HCMC: n=311; HP: n=162) was much larger than those of the semi-visible (HCMC: n=65; HP: n=43) and non-visible (HCMC: n=37; HP: n=10) FSWs in HCMC and HP. Non-visible FSWs in both cities were just as likely as visible and semi-visible FSWs to be HIV positive (HCMC: visible 14.5%, semi-visible 13.8%, non-visible 13.5%, p value = 0.982; HP: visible 35.2%, semi-visible 30.2%, non-visible 30.0%, p value = 0.801), to practice behaviors that put them at risk for contracting and transmitting HIV (injecting drug use-HCMC: visible 13.8%, semi-visible 12.3%, non-visible 5.4%, p value = 0.347; HP: visible 38.9%, semi-visible 23.3%, non-visible 30.0%, p value = 0.378, to have no condom use in the past month -HCMC only: visible 52.7%, semi-visible 63.1%, non-visible 48.6%, p value = 0.249) and to have symptoms of a sexually transmitted infection (STI) in the past year (HCMC: visible 16.1%, semi-visible 12.3%, non-visible 16.2%, p value = 0.742; HP: visible 13.6%, semi-visible 18.6%, non-visible 20.0%, p value = 0.640). There was a difference found among the visible, semi-visible and non-visible groups in HP for no past month condom use (visible 53.1%, semi-visible 79.1%, non-visible 60.0%, p value = 0.009). This study found that RDS was successful at recruiting hidden types of FSWs in Vietnam. Past reports of FSWs in Vietnam have assessed the more visible FSWs as being the most vulnerable and at risk for HIV. Although the number of visible FSWs is much higher than those of the semi and non-visible groups, this study found that the non-visible FSWs are very vulnerable to HIV infection. If prevention programs are targeting and responding to those who are most likely to be assessed (e.g., more visible types of FSWs) then this analysis indicates that a significant proportion of the FSW population at risk for HIV may not be receiving optimal HIV information and services.

Data Collection↗

PubMed2004

Solid-phase extraction-high-performance liquid chromatography-ion trap mass spectrometry for analysis of trace concentrations of macrolide antibiotics in natural and waste water matrices.

A method using solid-phase extraction (SPE) combined with high-performance liquid chromatography-ion trap tandem mass spectrometry (LC-MS-MS) has been developed for determination of trace concentrations of erythromycin-H2O (ETM-H2O), roxithromycin (RTM) and tylosin (TLS) in natural and waste water matrices. These macrolides (MLs) were extracted from water samples using Oasis HLB cartridges, and the average recovery was 93.6 +/- 8.6, 92.1 +/- 10.0, and 94.3 +/- 8.9% for ETM-H2O, RTM and TLS in surface water, respectively. For water from the influent of a wastewater treatment plant (WWTP), the average recovery was 84.8 +/- 14.0, 83.2 +/- 13.1, and 86.1 +/- 13.4% for ETM-H2O, RTM and TLS, respectively. Method detection limits in a natural water matrices were 0.07, 0.03, and 0.05 microg/l for ETM-H2O, RTM, and TLS, respectively. Fragment or product ions from MS spectra using in-source collision-induced dissociation and MS-MS spectra have been identified. The accuracy and day-to-day variation of the method fell within acceptable ranges. The method was evaluated by studying the occurrence of the three macrolides on a river and a WWTP in northern Colorado. None of the antibiotics were detected in the stream except immediately downstream of a WWTP, a result consistent with their presence in the influent and effluent of the treatment facility.

Anti-Bacterial Agents↗

PubMed2006

Tumour lysis syndrome in solid tumours.

Tumour lysis syndrome (TLS) is an oncological emergency that results from massive cytolysis of malignant cells with a sudden release of their cellular contents, such as intracellular ions and metabolic by-products, into the systemic circulation. This syndrome is common in tumours with rapid cell turnover and growth rates, and in bulky tumours with high sensitivity to antineoplastic treatments. It is, therefore, a well-recognised clinical problem in haematological malignancies. It is rarely observed in solid tumours. Here, published studies are reviewed, beginning with the first report of TLS in solid tumours. Reported solid TLS cases are evaluated according to their common features and differences, and their similarities with those seen in haematological malignancies. Basic principles for the prevention and management of TLS are mentioned, with particular emphasis on solid tumours.

Cell Proliferation↗

PubMed2005

Increased angiogenic capabilities of endothelial cells from microvessels of malignant human gliomas.

Vascular endothelial cells (ECs) that initiate tumor angiogenesis may acquire distinct properties after conditioning in tumor microenvironment as compared to ECs in non-malignant tissues. Thus far, most in vitro studies of angiogenesis used ECs isolated from normal tissues, which may not fully represent the nature of ECs in tumor vasculature. In this study, glioma-derived microvascular ECs (GDMEC) were purified from human glioma tissues by incubating with magnetic beads coated with anti-CD105 antibody and highly pure (98%) preparations of GDMEC were obtained. These cells exhibited typical EC phenotype, and proliferated rapidly in culture. Interestingly, GDMEC expressed higher levels of VEGF receptors, flt-1 and flk-1, as compared to an established human EC cell line ECV304 and primary human umbilical vascular EC (HUVEC). Functionally, GDMEC were capable of forming intercellular junctions and tubule-like structures (TLS) of various sizes. Stimulation by VEGF further promoted TLS formation with diverse tubular walls by GDMEC. In contrast, TLS formed by ECV304 and HUVEC showed significantly different features. We further observed that Nordy, a synthetic lipoxygenase inhibitor, potently inhibited TLS formation by GDMEC. The results suggest that isolation of highly pure ECs derived from tumor tissues is more appropriate for studies of tumor angiogenesis and for test of potential anti-cancer therapeutic targets.

Astrocytoma↗

PubMed2005

Adduct size limits efficient and error-free bypass across bulky N2-guanine DNA lesions by human DNA polymerase eta.

The N2 position of guanine (G) is one of the major sites for DNA modification by various carcinogens. Eight oligonucleotides with varying adduct bulk at guanine N2 were analyzed for catalytic efficiency and fidelity with human DNA polymerase (pol) eta, which is involved in translesion synthesis (TLS). Pol eta effectively bypassed N2-methyl(Me)G, N2-ethyl(Et)G, N2-isobutyl(Ib)G, N2-benzyl(Bz)G, and N2-CH2(2-naphthyl)G but was severely blocked at N2-CH2(9-anthracenyl)G (N2-AnthG) and N2-CH2(6-benzo[a]pyrenyl)G (N2-BPG). Steady-state kinetic analysis showed proportional decreases of kcat/Km in dCTP insertion opposite N2-AnthG and N2-BPG (73 and 320-fold) and also kcat/Km in next-base extension from a C paired with each adduct (15 and 51-fold relative to G). Frequencies of dATP misinsertion and extension beyond mispairs were also proportionally increased (70 and 450-fold; 12 and 44-fold) with N2-AnthG and N2-BPG, indicating the effect of adduct bulk on blocking and misincorporation in TLS by pol eta. N2-AnthG and N2-BPG also greatly decreased the pre-steady-state kinetic burst rate (25 and 125-fold) compared to unmodified G. N2-AnthG decreased dCTP binding affinity (2.6-fold) and increased DNA substrate binding affinity. These results and the small kinetic thio effects (S(p)-dCTPalphaS) suggest that the early steps, possibly conformational change, are interfered with by the bulky adducts. In contrast, human pol delta bypassed adducts effectively up to N2-EtG but was strongly blocked by N2-IbG and larger adducts. We conclude that TLS DNA polymerases may be required for the efficient bypass of pol delta-blocking N2-G adducts bulkier than N2-EtG in human cells, and the bulk size can be a major factor for efficient and error-free bypass at these adducts by TLS DNA polymerases.

Binding Sites↗

PubMed2005

Idiosyncratic behaviour of tRNA-like structures in translation of plant viral RNA genomes.

Tobacco mosaic virus (TMV) and Nemesia ring necrosis virus (NeRNV) belong to the Tobamoviridae and Tymoviridae families, respectively. Although their RNAs present different 5'-untranslated regions and different family-specific genomic organizations, they share common 3'-ends organized into three consecutive pseudoknot structures followed by a histidylatable tRNA-like structure (TLS). We investigate here whether the histidine residue becomes incorporated into viral proteins and if the TLSs of TMV and NeRNV play a role in viral translation. Our results indicate that, regardless of the genomic context, the histidine moiety does not become incorporated in proteins via ribosomal translation, and that disruption of the TLS in either viral RNA does not perturb the viral translation patterns. In the light of the present data and of previous results on tymoviral TLSVal and bromoviral TLSTyr showing differential effects on translation, we suggest that the key role for the TLS in promoting translation initiation appears to be dictated by the TLS architecture and identity.

Genome, Viral↗

PubMed2005

Analysis of the spontaneous mutator phenotype associated with 20S proteasome deficiency in S. cerevisiae.

Besides its role as a major recycler of unfolded or otherwise damaged intracellular proteins, the 26S proteasome functions as a regulator of many vital cellular processes and is postulated as a target for antitumor drugs. It has previously been shown that dysfunction of the catalytic core of the 26S proteasome, the 20S proteasome, causes a moderate increase in the frequency of spontaneous mutations in yeast [A. Podlaska, J. McIntyre, A. Skoneczna, E. Sledziewska-Gojska, The link between proteasome activity and postreplication DNA repair in Saccharomyces cerevisiae. Mol. Microbiol. 49 (2003) 1321-1332]. Here we show the results of genetic analysis, which indicate that the mutator phenotype caused by the deletion of UMP1, encoding maturase of 20S proteasome, involves members of the RAD6 epistasis group. The great majority of mutations occurring spontaneously in yeast cells deficient in 20S proteasome function are connected with the unique Rad6/Rad18-dependent error-prone translesion DNA synthesis (TLS) requiring the activities of both TLS polymerases: Pol eta and Pol zeta. Our results suggest the involvement of proteasomal activity in the limitation of this unique error-prone TLS mechanism in wild-type cells. On the other hand, we found that the mutator phenotypes caused by deficiency in Rad18 and Rad6, are largely alleviated by defects in proteasome activities. Since the mutator phenotypes produced by deletion of RAD6 and RAD18 require Pol zeta and Siz1/Ubc9-dependent sumoylation of PCNA, our results suggest that proteasomal dysfunction limits sumoylation-dependent error-prone activity of Pol zeta. Taken together, our findings strongly support the idea that proteolytic activity is involved in modulating the balance between TLS mechanisms functioning during DNA replication in S. cerevisiae.

Base Sequence↗