National Cancer Institute®
Last Modified: February 1, 2002
UI - 11731874
AU - Di Donato S; Gellera C; Mariotti C
TI - The complex clinical and genetic classification of inherited ataxias. II. Autosomal recessive ataxias.
SO - Neurol Sci 2001 Jun;22(3):219-28
AD - Division of Biochemistry and Genetics, C. Besta National Neurological Institute, Via Celoria 11, I-20133 Milan, Italy.
Autosomal recessive ataxias are a heterogeneous group of rare neurodegenerative diseases characterized by early onset cerebellar ataxia associated with various neurologic, ophthalmologic and systemic signs. In comparison with autosomal dominant ataxias, the group of recessive ataxias is less extensively characterized. In fact, only a few conditions have been genetically characterized. The pathogenesis of these forms is associated with a "loss of function" of specific cellular proteins involved in metabolic homeostasis, cell cycle, and DNA repair/protection processing. The two most common autosomal recessive ataxias, in European countries, are Friedreich's ataxia and ataxia telangiectasia. Other forms are much less frequent, and include ataxia with vitamin E deficiency, abetalipoproteinemia. Refsum's disease, spastic ataxia, infantile onset spinocerebellar ataxia, and ataxia with oculomotor apraxia. These pathological conditions, although extremely rare, have nevertheless to be carefully considered in differential diagnosis, not only for correct nosographical classification, but particularly, for specific prognostic and therapeutic implications. Some of these diseases exhibit a peculiar regional distribution. An updated review of the clinical, genetic, and pathogenic aspects of recessive ataxias is presented. Specific management problems with respect to diagnosis and genetic counseling are discussed.
UI - 11821961
AU - Bradshaw PS; Condie A; Matutes E; Catovsky D; Yuille MR
TI - Breakpoints in the ataxia telangiectasia gene arise at the RGYW somatic hypermutation motif.
SO - Oncogene 2002 Jan 17;21(3):483-7
AD - Academic Department of Haematology and Cytogenetics, Institute of Cancer Research, Sutton, Surrey, UK.
The mature sporadic T-cell malignancy, T-cell prolymphocytic leukemia (T-PLL) is remarkable for frequently harbouring somatic mutations of the Ataxia Telangiectasia (A-T) gene, ATM. Because some data suggest ATM is frequently rearranged in T-PLL, it was decided to investigate such rearrangements in detail by cloning breakpoints. Among 17 T-PLL tumour samples, three rearrangements were detected by Southern blotting. Two cases harboured a unique type of intragenic duplication in which breakpoints arose at the consensus sequence RGYW/WRCY. The third case harboured a large deletion terminating within the ATM gene. Also, 13 T-cell acute lymphoblastic leukemia (T-ALL) samples were examined and one sample harboured a deletion- insertion with the RGYW motif at the breakpoint in ATM. This is the first known deleterious mutation detected in ATM in T-ALL. Interestingly, the RGYW motif is the signal for a cell-cycle regulated DNA double strand break (DSB) that initiates somatic hypermutation of immunoglobulin and, probably, T-cell receptor genes. The structures of the ATM duplications suggest they may arise from an error in somatic hypermutation. We suggest that aberrant components of somatic hypermutation may contribute to the defective DSB repair characteristic of cancer.
UI - 11741320
AU - Theard D; Coisy M; Ducommun B; Concannon P; Darbon JM
TI - Etoposide and adriamycin but not genistein can activate the checkpoint kinase Chk2 independently of ATM/ATR.
SO - Biochem Biophys Res Commun 2001 Dec 21;289(5):1199-204
AD - Laboratoire de Biologie Cellulaire et Moleculaire du Controle de la Proliferation, UMR 5088 CNRS, Universite Paul Sabatier, Bat 4R3B1, 118 route de Narbonne, Toulouse, 31062, France.
We have investigated the effects of three unrelated topoisomerase 2 inhibitors, genistein, adriamycin, and etoposide, on phosphorylation/activation of the checkpoint kinase Chk2 in normal or ATM-deficient (ATM-) human fibroblasts and in cells overexpressing a catalytically inactive ATR kinase. We demonstrate that genistein activates Chk2 in a strictly ATM-dependent manner, whereas etoposide and adriamycin can trigger Chk2 activation in long-term cultures of ATM- cells. Moreover, these two latter genotoxic compounds were found to activate Chk2 in fibroblasts expressing the dominant negative form of ATR. We also report a significant decrease in the accumulation in G2-phase of ATM- cells when genistein did not activate Chk2. In conclusion, our results strongly support that activation of Chk2 could be dependent on the type and/or extent of DNA damage and under the control of either an ATM-dependent or an ATM and, maybe, an ATR-independent pathway.
UI - 10454555
AU - Smith GC; d'Adda di Fagagna F; Lakin ND; Jackson SP
TI - Cleavage and inactivation of ATM during apoptosis.
SO - Mol Cell Biol 1999 Sep;19(9):6076-84
AD - Wellcome/CRC Institute and Department of Zoology, University of Cambridge, Cambridge, United Kingdom.
The activation of the cysteine proteases with aspartate specificity, termed caspases, is of fundamental importance for the execution of programmed cell death. These proteases are highly specific in their action and activate or inhibit a variety of key protein molecules in the cell. Here, we study the effect of apoptosis on the integrity of two proteins that have critical roles in DNA damage signalling, cell cycle checkpoint controls, and genome maintenance-the product of the gene defective in ataxia telangiectasia, ATM, and the related protein ATR. We find that ATM but not ATR is specifically cleaved in cells induced to undergo apoptosis by a variety of stimuli. We establish that ATM cleavage in vivo is dependent on caspases, reveal that ATM is an efficient substrate for caspase 3 but not caspase 6 in vitro, and show that the in vitro caspase 3 cleavage pattern mirrors that in cells undergoing apoptosis. Strikingly, apoptotic cleavage of ATM in vivo abrogates its protein kinase activity against p53 but has no apparent effect on the DNA binding properties of ATM. These data suggest that the cleavage of ATM during apoptosis generates a kinase-inactive protein that acts, through its DNA binding ability, in a trans-dominant-negative fashion to prevent DNA repair and DNA damage signalling.
UI - 11587230
AU - Viniou N; Terpos E; Rombos J; Vaiopoulos G; Nodaros K; Stamatopoulos K;
TI - Meletis J; Yataganas X Acute myeloid leukemia in a patient with ataxia-telangiectasia: a case report and review of the literature.
SO - Leukemia 2001 Oct;15(10):1668-70
UI - 11850813
AU - Bar-Shira A; Rashi-Elkeles S; Zlochover L; Moyal L; Smorodinsky NI;
TI - Seger R; Shiloh Y ATM-dependent activation of the gene encoding MAP kinase phosphatase 5 by radiomimetic DNA damage.
SO - Oncogene 2002 Jan 24;21(5):849-55
AD - The David and Inez Myers Laboratory for Genetic Research, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Cellular responses to DNA damage are mediated by an extensive network of signaling pathways. The ATM protein kinase is a master regulator of the response to double-strand breaks (DSBs), the most cytotoxic DNA lesion caused by ionizing radiation. ATM is the protein missing or inactive in patients with the pleiotropic genetic disorder ataxia-telangiectasia (A-T). A major response to DNA damage is altered expression of numerous genes. While studying gene expression in control and A-T cells following treatment with the radiomimetic chemical neocarzinostatin (NCS), we identified an expressed sequence tag that represented a gene that was induced by DSBs in an ATM-dependent manner. The corresponding cDNA encoded a dual specificity phosphatase of the MAP kinase phosphatase family, MKP-5. MKP-5 dephosphorylates and inactivates the stress-activated MAP kinases JNK and p38. The phosphorylation-dephosphorylation cycle of JNK and p38 by NCS was attenuated in A-T cells. Thus, ATM modulates this cycle in response to DSBs. These results further highlight ATM as a link between the DNA damage response and major signaling pathways involved in proliferative and apoptotic processes.
UI - 11809797
AU - Xu B; Kim ST; Lim DS; Kastan MB
TI - Two molecularly distinct G(2)/M checkpoints are induced by ionizing irradiation.
SO - Mol Cell Biol 2002 Feb;22(4):1049-59
AD - Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Cell cycle checkpoints are among the multiple mechanisms that eukaryotic cells possess to maintain genomic integrity and minimize tumorigenesis. Ionizing irradiation (IR) induces measurable arrests in the G(1), S, and G(2) phases of the mammalian cell cycle, and the ATM (ataxia telangiectasia mutated) protein plays a role in initiating checkpoint pathways in all three of these cell cycle phases. However, cells lacking ATM function exhibit both a defective G(2) checkpoint and a prolonged G(2) arrest after IR, suggesting the existence of different types of G(2) arrest. Two molecularly distinct G(2)/M checkpoints were identified, and the critical importance of the choice of G(2)/M checkpoint assay was demonstrated. The first of these G(2)/M checkpoints occurs early after IR, is very transient, is ATM dependent and dose independent (between 1 and 10 Gy), and represents the failure of cells which had been in G(2) at the time of irradiation to progress into mitosis. Cell cycle assays that can distinguish mitotic cells from G(2) cells must be used to assess this arrest. In contrast, G(2)/M accumulation, typically assessed by propidium iodide staining, begins to be measurable only several hours after IR, is ATM independent, is dose dependent, and represents the accumulation of cells that had been in earlier phases of the cell cycle at the time of exposure to radiation. G(2)/M accumulation after IR is not affected by the early G(2)/M checkpoint and is enhanced in cells lacking the IR-induced S-phase checkpoint, such as those lacking Nbs1 or Brca1 function, because of a prolonged G(2) arrest of cells that had been in S phase at the time of irradiation. Finally, neither the S-phase checkpoint nor the G(2) checkpoints appear to affect survival following irradiation. Thus, two different G(2) arrest mechanisms are present in mammalian cells, and the type of cell cycle checkpoint assay to be used in experimental investigation must be thoughtfully selected.
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