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PubMed1998

Genotype-phenotype relationships in ataxia-telangiectasia and variants.

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity, and cancer predisposition. A-T cells are sensitive to ionizing radiation and radiomimetic chemicals and fail to activate cell-cycle checkpoints after treatment with these agents. The responsible gene, ATM, encodes a large protein kinase with a phosphatidylinositol 3-kinase-like domain. The typical A-T phenotype is caused, in most cases, by null ATM alleles that truncate or severely destabilize the ATM protein. Rare patients with milder manifestations of the clinical or cellular characteristics of the disease have been reported and have been designated "A-T variants." A special variant form of A-T is A-TFresno, which combines a typical A-T phenotype with microcephaly and mental retardation. The possible association of these syndromes with ATM is both important for understanding their molecular basis and essential for counseling and diagnostic purposes. We quantified ATM-protein levels in six A-T variants, and we searched their ATM genes for mutations. Cell lines from these patients exhibited considerable variability in radiosensitivity while showing the typical radioresistant DNA synthesis of A-T cells. Unlike classical A-T patients, these patients exhibited 1%-17% of the normal level of ATM. The underlying ATM genotypes were either homozygous for mutations expected to produce mild phenotypes or compound heterozygotes for a mild and a severe mutation. An A-TFresno cell line was found devoid of the ATM protein and homozygous for a severe ATM mutation. We conclude that certain "A-T variant" phenotypes represent ATM mutations, including some of those without telangiectasia. Our findings extend the range of phenotypes associated with ATM mutations.

Adult↗
PubMed2004

ATM is required for telomere maintenance and chromosome stability during Drosophila development.

ATM is a large, multifunctional protein kinase that regulates responses required for surviving DNA damage: including DNA repair, apoptosis, and cell cycle checkpoints. Here, we show that Drosophila ATM function is essential for normal adult development. Extensive, inappropriate apoptosis occurs in proliferating atm mutant tissues, and in clonally derived atm mutant embryos, frequent mitotic defects were seen. At a cellular level, spontaneous telomere fusions and other chromosomal abnormalities are common in atm larval neuroblasts, suggesting a conserved and essential role for dATM in the maintenance of normal telomeres and chromosome stability. Evidence from other systems supports the idea that DNA double-strand break (DSB) repair functions of ATM kinases promote telomere maintenance by inhibition of illegitimate recombination or fusion events between the legitimate ends of chromosomes and spontaneous DSBs. Drosophila will be an excellent model system for investigating how these ATM-dependent chromosome structural maintenance functions are deployed during development. Because neurons appear to be particularly sensitive to loss of ATM in both flies and humans, this system should be particularly useful for identifying cell-specific factors that influence sensitivity to loss of dATM and are relevant for understanding the human disease, ataxia-telangiectasia.

Animals↗
PubMed2004

Update on the proteasome inhibitor bortezomib in hematologic malignancies.

The ubiquitin-proteasome system plays a crucial role in eukaryotic cells in maintaining protein homeostasis. Through the disruption of a variety of pathways and cell cycle checkpoints, proteasome inhibition leads to apoptosis and in experimental models can overcome chemoresistance. Bortezomib is the first of its class of proteasome inhibitors tested in humans that showed promising activity in several tumor types, and especially in hematologic malignancies, in phase I studies. The remarkable results obtained in phase II studies in multiple myeloma (MM) led to its fast-track approval by the US Food and Drug Administration in May 2003 for relapsed MM. More recent observation also revealed promising activity in non-Hodgkin's lymphoma. This review will explore the rationale for the use of bortezomib in hematologic malignancies as well as provide an update on the results of ongoing studies and future directions for the use of this new agent in hematologic malignancies. The mechanism of action of bortezomib and its nonoverlapping toxicity profile make it a very appealing drug for combination with other chemotherapeutic or biologic agents. Bortezomib represents an excellent example of how progress in understanding the biology of cancer cells can impact clinical practice and lead toward a new era of rational therapeutics.

Antineoplastic Agents↗
PubMed2002

Constitutive association of BRCA1 and c-Abl and its ATM-dependent disruption after irradiation.

BRCA1 plays an important role in mechanisms of response to double-strand breaks, participating in genome surveillance, DNA repair, and cell cycle checkpoint arrests. Here, we identify a constitutive BRCA1-c-Abl complex and provide evidence for a direct interaction between the PXXP motif in the C terminus of BRCA1 and the SH3 domain of c-Abl. Following exposure to ionizing radiation (IR), the BRCA1-c-Abl complex is disrupted in an ATM-dependent manner, which correlates temporally with ATM-dependent phosphorylation of BRCA1 and ATM-dependent enhancement of the tyrosine kinase activity of c-Abl. The BRCA1-c-Abl interaction is affected by radiation-induced modification to both BRCA1 and c-Abl. We show that the C terminus of BRCA1 is phosphorylated by c-Abl in vitro. In vivo, BRCA1 is phosphorylated at tyrosine residues in an ATM-dependent, radiation-dependent manner. Tyrosine phosphorylation of BRCA1, however, is not required for the disruption of the BRCA1-c-Abl complex. BRCA1-mutated cells exhibit constitutively high c-Abl kinase activity that is not further increased on exposure to IR. We suggest a model in which BRCA1 acts in concert with ATM to regulate c-Abl tyrosine kinase activity.

Ataxia Telangiectasia Mutated Proteins↗
PubMed1996

Cloning of rat GADD45 gene and induction analysis following ionizing radiation in vivo.

A gene encoded GADD45 was isolated from rat and revealed four exons along with a p53 binding consensus sequence and a putative AP-1 site in the third intron. This suggests that the rat GADD45 gene is also involved in the p53 signal pathway related to the G1 cell cycle checkpoint. The rat GADD45 mRNA was induced within 30 min in liver and increased as a function of gamma-irradiation. We found that mRNA expression differed substantially in a variety of tissues (brain, liver, kidney, and spleen). The finding of in vivo induction of GADD45 gene may provide insight into the role of GADD45 gene in DNA repair.

Alkylating Agents↗
PubMed2005

The 2,5 oligoadenylate synthetase/RNaseL pathway is a novel effector of BRCA1- and interferon-gamma-mediated apoptosis.

BRCA1 has been reported to have roles in DNA damage repair, cell cycle checkpoint control, transcriptional regulation and ubiquitination. We have previously demonstrated that BRCA1 is a potent activator of a subset of interferon (IFN)-regulated genes and that BRCA1 synergistically activated a number of these genes in the presence of IFN-gamma, but not type I IFNs. Here we report that one of these targets, 2,5 oligoadenylate synthetase (2,5 OAS), is a mediator of BRCA1/IFN-gamma-induced apoptosis. We show that the induction of 2,5 OAS in response to IFN-gamma is BRCA1 and STAT1 dependent. Consistent with a role as a negative regulator of proliferation, transient transfection of 2,5 OAS into breast cancer cell lines results in decreased colony growth and apoptosis. Furthermore we show that IFN-gamma-induced apoptosis is dependent on functional BRCA1 and STAT1 and we demonstrate that IFN-gamma-induced apoptosis is dependent on 2,5 OAS induction. 2,5 OAS is the only known upstream regulator of RNaseL, a recently identified hereditary prostate tumour suppressor gene implicated in apoptosis. We propose that BRCA1 may be an upstream regulator of RNaseL, acting in concert with IFN-gamma to transcriptionally activate 2,5 OAS, leading to the downstream activation of RNaseL and apoptosis.

2',5'-Oligoadenylate Synthetase↗
PubMed2004

p53, p16 and cyclin D1: molecular determinants of radiotherapy treatment response in oral carcinoma.

Management of oral cancer by radiotherapy has witnessed promising advances in the past few years, with patient-tailored radio fractionation regimens. Different fractionation schedules, conventional and altered regimes, have been used in curative radiotherapy. Although contribution of biological markers on radio response has been evaluated, its unique influence on various radio fractionation schemes has not been accounted so far. Our study analyses a set of proteins that previously demonstrated radio response influence for their possible prognostic value in decision-making process between the respective fractionation schemes. Expression patterns of regulatory proteins such as p53, cyclin D1, p16, Cdk4, p21, Rb, bcl-2 and PCNA were determined by immunohistochemistry utilizing monoclonal antibodies in 125 patients who received curative radiotherapy dose. Among these 125 patients, 90 (72%) received altered fractionation, whereas 35 (28%) received conventional fractionation. p53 over-expression correlated with local treatment failure among the patients treated with conventional fractionation whereas cyclin D1 over-expression and p16 underexpression were associated with local treatment failure as well as overall survival in altered fractionation treated cases. Our findings suggest that wild-type p53 status may be an important parameter for achieving high local control in those patients undergoing conventional fractionation, where as intact p16 and cyclin D1 status may be beneficial for effective local control in patients who are treated with altered fractionation. Furthermore, it can be assumed that conventional fractionation employs p53-mediated apoptosis, whereas altered fractionation activates the functional G1 cell-cycle checkpoint for tumor growth suppression.

Adult↗
PubMed1997

The role of p53, p21WAF1/C1PI, and bcl-2 in radioresistant colorectal carcinoma.

Genetic alterations in the p53 tumor suppressor gene are common in human colorectal cancers, occurring in approximately 70% of tumors. In vitro studies have shown that wild-type p53 is involved in controlling cell cycle checkpoint functions and apoptosis involved in the cytotoxic response induced by ionizing radiation and several anticancer chemotherapeutic agents. Wild-type p53 protein can transcriptionally activate the WAF gene, which encodes a cyclin-dependent kinase inhibitory protein, p21WAF1/C1PI protein, and transcriptionally repress the bcl-2 gene, which encodes an inhibitor of apoptosis. To learn more about the in vivo relationship between p53 protein and the expression of p21WAF1/C1PI and bcl-2 proteins in human colorectal cancers treated with radiation therapy, we examined the expression of these proteins by immunohistochemistry in pre-irradiated biopsy specimens and surgical specimens with residual tumor of 27 patients with colorectal carcinoma. Cell proliferation was measured using Ki-67 expression in the tumor cells. The p53 protein was not detected in normal colorectal mucosa, but it was expressed in 21 of 27 (78%) of pre-irradiated tumor samples and in 19 of 27 (70%) of post-irradiated tumors. Expression of the bcl-2 protein in normal colorectal mucosa was confined to the basal epithelial cells of the crypts. Diffuse bcl-2 staining was detected in tumor cells in 13 of 27 (48%) of pre-irradiated samples and in 14 of 27 (52%) of post-irradiated samples. p21WAF1/C1PI expression was detected in 14 of 27 (52%) of pre-irradiated samples but only in 7 of 27 (26%) of post-irradiated samples. No inverse relationship between expression of p53 protein and abnormal bcl-2 expression was apparent. p21WAF1/C1PI was expressed in most nonproliferating Ki-67-negative epithelial cells at the apical tips of the crypts in normal colorectal mucosa, but not in proliferating Ki-67-positive cells of adjacent adenomatous mucosa. An inverse relationship between Ki-67 and p21WAF1/C1PI expression was observed in normal colorectal mucosa and adjacent adenomatous mucosa. After radiation therapy, p53 protein accumulation did not change among residual tumors in 18 cases (three of which were initially negative and remained negative); in four cases there was a significant increase, and five cases had a substantial decrease of p53 expression. Aberrant bcl-2 expression is not correlated with expression of p53 and does not increase significantly in post-irradiated tumor cells. p21WAF1/C1PI expression is markedly reduced in tumor cells that survive radiation therapy.

Adenocarcinoma↗
PubMed2004

Skp2 and p27kip1 expression in melanocytic nevi and melanoma: an inverse relationship.

BACKGROUND: S-phase kinase associated protein-2 (Skp2) ubiquitin ligase p45(SKP2) is important in the degradation of p27kip1 (a cyclin dependent kinase inhibitor) and progression through the G1-S cell-cycle checkpoint. Low levels of p27 and high levels of Skp2 are related to poor prognosis in some cancers. METHODS: Clinicopathologic features and immunohistochemical expression of Skp2 and p27kip1 were investigated in 198 melanocytic proliferations: 21 melanocytic nevi, 23 melanoma in situ, 119 primary melanoma, and 35 metastatic melanoma samples. Comparative and survival analyses were performed. RESULTS: Progressive and significant increases and decreases in the nuclear expression of Skp2 and p27kip1, respectively, was identified moving from melanocytic nevi (0.05 +/- 0.2/85 +/- 15) to melanoma in situ (3 +/- 2/45 +/- 20) to primary cutaneous melanoma (12 +/- 9/30 +/- 25) to metastatic melanoma (25 +/- 15/15 +/- 20) (p < or = 0.006). Expression of these proteins also significantly correlated with increasing American Joint Committee on Cancer (AJCC) T (tumor) classification and AJCC stage (p < or = 0.01). Moreover, the level of these two proteins exhibited a significant inverse relationship (r = -0.4, p = 0.0001). Skp2 cytoplasmic labeling index of >20% predicted worse 10-year overall survival (38% vs. 86%, p = 0.04) in primary melanoma. Neither p27 nor Skp2 nuclear expression impacted significantly on prognosis. CONCLUSIONS: Gain of Skp2 and loss of p27kip1 protein expression are implicated in melanoma progression where the level of p27kip1 may be regulated by targeted proteolysis via Skp2. Cytoplasmic expression of Skp2 defines a subset of aggressive melanomas and could represent another pathway of deregulation of the cell cycle.

Adult↗
PubMed1992

A fundamental role for cell cycle regulation in the chemosensitivity of cancer cells?

The majority of clinically effective anticancer drugs inhibit some aspect of the machinery responsible for DNA replication and chromosome segregation. Drug action also arrests cells at defined points in the cell cycle called checkpoints. These checkpoints ensure that subsequent cell cycle events are inhibited until the inflicted damage is repaired. The fidelity of checkpoint control and susceptibility of cells to apoptosis while repair is underway may be important factors in the success of chemotherapy. We discuss these concepts and focus particularly on possible applications to improved antitumor therapy with DNA damaging agents.

Antineoplastic Agents↗
PubMed2005

Gadd45a expression induces Bim dissociation from the cytoskeleton and translocation to mitochondria.

Gadd45a, a p53- and BRCA1-regulated stress protein, has been implicated in the maintenance of genomic fidelity, probably through its roles in the control of cell cycle checkpoint and apoptosis. However, the mechanism(s) by which Gadd45a is involved in the induction of apoptosis remains unclear. We show here that inducible expression of Gadd45a protein causes dissociation of Bim, a Bcl2 family member, from microtubule-associated components and translocation to mitochondria. The Bim accumulation in mitochondria enhances interaction of Bim with Bcl-2, relieves Bax from Bcl-2-bound complexes, and subsequently results in release of cytochrome c into the cytoplasm. Suppression of endogenous Bim greatly inhibits Gadd45a induction of apoptosis. Interestingly, Gadd45a interacts with elongation factor 1alpha (EF-1alpha), a microtubule-severing protein that plays an important role in maintaining cytoskeletal stability, and inhibits EF-1alpha-mediated microtubule bundling, indicating that the interaction of Gadd45a with EF-1alpha disrupts cytoskeletal stability. A mutant form of Gadd45a harboring a deletion of EF-1alpha-binding domain fails to inhibit microtubule stability and to induce Bim translocation to mitochondria. Furthermore, coexpression of EF-1alpha antagonizes Gadd45a's property of suppressing cell growth and inducing apoptosis. These findings identify a novel link that connects stress protein Gadd45a to the apoptotic machinery and address the importance of cytoskeletal stability in apoptotic response to DNA damage.

Apoptosis↗
PubMed2000

Cancer risk and the ATM gene: a continuing debate.

Deficiencies in the ability of cells to sense and repair damage in individuals with rare genetic instability syndromes increase the risk of developing cancer. Ataxia-telangiectasia (A-T), such a condition, is associated with a high incidence of leukemia and lymphoma that develop in childhood. Although A-T is an autosomal recessive disorder, some penetrance appears in individuals with one mutated ATM gene (A-T carriers), namely, an increased risk of developing breast cancer. The gene mutated in A-T, designated ATM, is homologous to several DNA damage recognition and cell cycle checkpoint control genes from other organisms. Recent studies suggest that ATM is activated primarily in response to double-strand breaks, the major cytotoxic lesion caused by ionizing radiation, and can directly bind to and phosphorylate c-Abl, p53, and replication protein A (RPA). Analysis of ATM mutations in patients with A-T or with sporadic non-A-T cancers has suggested the existence of two classes of ATM mutation: null mutations leading to A-T and dominant negative missense mutations predisposing to cancer in the heterozygous state. Studies with A-T mouse models have helped determine the basis of lymphoid tumorigenesis in A-T and have shown that ATM plays a critical role in maintaining genetic stability by ensuring high-fidelity execution of chromosomal events. Thus, ATM appears to act as a caretaker of the genome.

Ataxia Telangiectasia↗
PubMed2003

The p53 tumor suppressor gene and nuclear protein: basic science review and relevance in the management of bladder cancer.

PURPOSE: An extensive body of literature regarding p53 has accumulated during the last 2 decades. The cellular mechanisms of p53 are complex yet well-defined, whereas its clinical usefulness in the management of bladder cancer remains controversial. We outline the basic constitutive functions of p53 and summarize its current role in the management of transitional cell carcinoma of the bladder. MATERIALS AND METHODS: We conducted a MEDLINE based literature review concerning the fundamental mechanisms of p53 and its role in the management of bladder cancer. RESULTS: The p53 gene is a tumor suppressor gene that acts as "guardian of the genome." Many diverse cellular events, including DNA damage and hypoxia, activate the p53 gene. The p53 protein functions as a transcription factor, regulating downstream genes involved in cell cycle arrest, DNA repair and programmed cell death. Loss of p53 function confers genomic instability, impaired apoptosis and diminished cell cycle restraint. Therefore, p53 mutations select for certain critical features of malignancy. Alteration of P53 is the most common mutation in human cancer. Roughly half of all human malignancies, including many urological cancers, exhibit p53 mutations. In bladder cancer p53 mutations have been associated with higher tumor grade and advanced stage, as well as progression of superficial disease to muscle invasion. Moreover, p53 nuclear over expression appears to be an independent predictor of disease progression and decreased survival after cystectomy. CONCLUSIONS: The importance of p53 mutation in tumor cell biology is irrefutable. Wild-type p53 mediates imperative functions such as regulation of the cell cycle and programmed cell death. Deficiency of p53 function by mutation or inactivation abrogates normal cell cycle checkpoints and apoptosis, generating a favorable milieu for genomic instability and carcinogenesis. However, despite the manifest importance of p53 in human malignancy, its current role in the management of bladder cancer appears somewhat limited. A multitude of retrospective studies have associated p53 mutations with adverse outcomes in superficial and muscle invasive disease. Nonetheless, randomized prospective studies are needed to determine the potential clinical implications of p53 in bladder cancer.

Animals↗
PubMed1993

Induction of cellular p53 activity by DNA-damaging agents and growth arrest.

The tumor suppressor p53 can function as a sequence-specific transcription factor and is required for activation by ionizing radiation (IR) of one or more downstream effector genes, such as the human GADD45 gene. One important consequence of IR that is probably mediated by these downstream effector genes is activation of the p53-mediated G1 cell cycle checkpoint. While the induction of reporter constructs containing p53-binding sites has already been demonstrated with p53 expression vectors, we have now demonstrated the direct activation of such a construct after treatment of the human RKO line, which has a normal p53 phenotype, with various types of DNA-damaging agents and also after growth arrest produced by medium depletion (starvation). IR, UV radiation, and methylmethane sulfonate were found to induce p53 activity when a stably integrated reporter construct containing functional p53-binding sites was used and also in mobility shift assays with a p53-binding site from the GADD45 gene, and IR-inducible gene previously associated with growth arrest. The same cell treatments that induced this p53 activity also caused an increase in cellular p53 protein levels. The response in cells lacking normal p53 or in RKO cells expressing a dominant negative mutant p53 was markedly reduced. Interestingly, the spectrum of effective inducing agents for the above-described experiments was similar to that which induces GADD45 either in cells with a normal p53 status or, with the exception of IR, in cells lacking normal p53. These results indicate a role for p53 in the IR pathway, which is completely p53 dependent, and in other genotoxic stress responses, in which p53 has a cooperative effect but is not required.

Animals↗
PubMed2006

Autophosphorylation at serine 1987 is dispensable for murine Atm activation in vivo.

The ATM (ataxia telangiectasia mutated) protein kinase is activated under physiological and pathological conditions that induce DNA double-strand breaks (DSBs). Loss of ATM or failure of its activation in humans and mice lead to defective cellular responses to DSBs, such as cell cycle checkpoints, radiation sensitivity, immune dysfunction, infertility and cancer predisposition. A widely used biological marker to identify the active form of ATM is the autophosphorylation of ATM at a single, conserved serine residue (Ser 1981 in humans; Ser 1987 in mouse). Here we show that Atm-dependent responses are functional at the organismal and cellular level in mice that express a mutant form of Atm (mutation of Ser to Ala at position 1987) as their sole Atm species. Moreover, the mutant protein does not exhibit dominant-negative interfering activity when expressed physiologically or overexpressed in the context of Atm heterozygous mice. These results suggest an alternative mode for stimulation of Atm by DSBs in which Atm autophosphorylation at Ser 1987, like trans-phosphorylation of downstream substrates, is a consequence rather than a cause of Atm activation.

Animals↗
PubMed2005

Interplay between septin organization, cell cycle and cell shape in yeast.

Septins are conserved filament-forming proteins that assemble into cortical cytoskeletal structures in animal and fungal cells. Although rapid progress has been made into the functions of septins, the mechanisms governing their localization and organization remain mysterious. In Saccharomyces cerevisiae, Cdc42p organizes the septin cytoskeleton into a ring in preparation for bud formation, following which septins remain as a collar at the mother-bud neck. We have dissected the phenotype of cdc42(V36T,K94E) cells that display an aberrant cell shape correlated with the development of ectopic septin caps and rings within the bud. The results suggest that a well-assembled septin cortex plays a novel role in directing growth to shape the nascent bud, and that a disorganized septin cortex directs improper growth generating an aberrant neck. Conversely, we found that the elongated bud shape arising as a result of the morphogenesis checkpoint cell cycle delay that accompanies septin perturbation can feed back to exacerbate minor defects in septin organization, by maintaining a bud-tip-localized septin assembly activity that competes with the neck-localized septin cortex. Using this exacerbation as a tool, we uncovered septin organization defects in many mutants not previously known to display such defects, expanding the cast of characters involved in proper assembly of the septin cortex to include CLN1, CLN2, BNI1, BNI4, BUD3, BUD4 and BUD5.

Cell Cycle↗
PubMed1998

Sensitivity to cisplatin and platinum-containing compounds of Schizosaccharomyces pombe rad mutants.

The role of genes that affect response to radiation in determining sensitivity to platinum-containing compounds was studied using a panel of 23 strains of the yeast Schizosaccharomyces pombe. The radiation-hypersensitive mutants all had the same genetic background and most of them contained mutations that disabled either cell cycle checkpoints or DNA repair. The tested platinum compounds included cisplatin and two complexes containing diaminocyclohexane (oxaliplatin and tetraplatin), two ammine/cyclohexylamine complexes with different orientation of the leaving groups (JM216 and JM335) and a multinuclear platinum complex (BBR 3464). The cytotoxic effect of the selected platinum complexes was evaluated by using a microtiter growth inhibition assay with a 48 hr exposure to drug. The mutants fell into three groups with respect to sensitivity to cisplatin: four mutants (rad2, -7, -11, -15) exhibited minimal change in sensitivity; fifteen mutants (rad4-6, -8-10, -12-14, -16-17, -19-21, and -22) were 5.1-21.7-fold hypersensitive; only rad1 and -3 mutants, defective in checkpoints, and rad18, defective in repair, displayed a marked hypersensitivity. None of the mutants demonstrated appreciable change in sensitivity to JM216 presumably as a consequence of a lack of resistance of the wild-type strain, whereas a moderate increase in sensitivity to JM335 was observed for most of the mutants, and hypersensitivity to BBR3464 was observed only in rad1 and -3. No relevant changes in sensitivity to tetraplatin were observed. Most of the mutants, with the exception of rad2, -7, and -15, were hypersensitive to oxaliplatin. These findings demonstrate that specific mutations have disparate effects on the profile of sensitivity to different members of the same class of cytotoxic agents, which provides genetic evidence that different mechanisms are involved in differential cytotoxicity induced by Pt compounds. The results also demonstrate the utility of such a panel of mutants, constructed on the same genetic background, for detecting specific cellular response; presumably, this reflects the recognition or processing of specific DNA adducts. In conclusion, because the rad1 and rad3 gene products are determinants of cellular response to a large number of platinum-containing compounds, the present results support a critical role of genes involved in cell cycle control in cellular sensitivity to these agents.

Cell Cycle↗
PubMedDate not supplied

Ataxia-telangiectasia-like disorder (ATLD)-its clinical presentation and molecular basis.

Comparison of the clinical and cellular phenotypes of different genomic instability syndromes provides new insights into functional links in the complex network of the DNA damage response. A prominent example of this principle is provided by examination of three such disorders: ataxia-telangiectasia (A-T) caused by lack or inactivation of the ATM protein kinase, which mobilises the cellular response to double strand breaks in the DNA; ataxia-telangiectasia-like disease (ATLD), a result of deficiency of the human Mre11 protein; and the Nijmegen breakage syndrome (NBS), which represents defective Nbs1 protein. Mre11 and Nbs1 are members of the Mre11/Rad50/Nbs1 (MRN) protein complex. MRN and its individual components are involved in different responses to cellular damage induced by ionising radiation and radiomimetic chemicals, including complexing with chromatin and with other damage response proteins, formation of radiation-induced foci, and the induction of different cell cycle checkpoints. The phosphorylation of Nbs1 by ATM would indicate that ATM acts upstream of the MRN complex. Consistent with this were the suggestions that ATM could be activated in the absence of fully functional Nbs1 protein. In contrast, the regulation of some ATM target proteins, e.g. Smc1 requires the MRN complex as well as ATM. Nbs1 may, therefore, be both a substrate for ATM and a mediator of ATM function. Recent studies that indicate a requirement of the MRN complex for proper ATM activation suggest that the relationship between ATM and the MRN complex in the DNA damage response is yet to be fully determined. Despite the fact that both Mre11 and Nbs1 are part of the same MRN complex, deficiency in either protein in humans does not lead to the same clinical picture. This suggests that components of the complex may also act separately.

Alleles↗