Encyclopedia of Genetics || ATP (Adenosine Triphosphate)

More recent work has shown that ATM is linked more directly to this repair complex since the ATM protein phosphorylates Nbs1 protein following exposure of cells to damage. Malignant Disease in Ataxia Telangiectasia Patients An increased risk of developing malignant disease is an important feature of A-T. Indeed approximately 10±15% of all A-T patients develop a malignancy in childhood with the majority of these tumors being lymphoid in origin, including both B and T cell lymphoid tumors as well as Hodgkin disease. The ATM gene defect appears to allow either a higher level of formation of illegitimate chromosome translocations, involving recombination of T cell receptor (TCR) genes, in T lymphocytes compared with non-A-T individuals or a lower rate of removal of these translocations. Adult patients develop T-cell prolympho- cytic leukemia arising from a proliferating T-cell clone marked by a translocation involving one of two genes, TCL1 or MTCP1. Younger patients develop T-cell acute leukemia or T-cell lymphoma and it is likely that the propensity for chromosome translocation contributes to these. ATM mutations in A-T patients with leukemia and lymphoma are scattered across the ATM gene suggest- ing that a single position within the ATM-coding sequence is unlikely to be associated with occurrence of leukemia or lymphoma in A-T patients. Disruption of the hMre11/hRad50/Nbs1 complex through mutations in the NBS1 gene in patients with NBS also results in a high frequency of lymphoma in these individuals. Other tumors seen in A-T patients at a higher frequency than normal include various epithelial cell tumors and brain tumors, and also breast cancer in a few families. Cancer Risks of ATM Mutation Carriers in A-T Families Although ATM mutations in A-T patients predispose to lymphoid tumors the effect of the mutations may be numerically more important in the heterozygous state. Approximately 0.5±1% of the population carry an ATM mutation and carriers in A-T families have been reported to have an increased relative risk of breast cancer of three- to fourfold. In contrast to studies with carriers in A-T families, studies of patients with sporadic breast cancer have not shown convincingly that ATM mutation carriers have an increased relative risk for breast cancer. ATM Mutation in Sporadic Tumors ATM mutations also play a role in the development of some sporadic tumors including T-cell prolympho- cytic leukemia, B-cell chronic lymphocytic leukemia, and mantle cell lymphoma. Further Reading Ataxia Telangiectasia Mutation Database, http://www.vmre- search.org/atm.htm Ataxia Telangiectasia Society UK, http://www.atsociety.org.uk/ A-T Children's project (USA), http://www.atcp.org/ Banin S, Moyal L, Shieh S-Y et al. (1998) Enhanced phosphoryla- tion of p53 by ATM in response to DNA damage. Science 281: 1674±1677. Online Mendelian Inheritance in Man (OMIM), http://www3. ncbi.nlm.nih.gov/omim/ Sedgwick RP and Boder E (1991) Ataxia telangiectasia. In: de Jong JMBV (ed.) Handbook of Clinical Neurology: Hereditary Neuropathies and Spinocerebellar Atrophies, vol. 16, pp. 347±423. Amsterdam: Elsevier. Shiloh Y (1997) Ataxia telangiectasia and the Nijmegen breakage syndrome: related disorders but genes apart. Annual Review of Genetics 31: 635±662. Stewart GS, Maser RS, Stankovic T et al. (1999) The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell 99: 577±587. The A-T Appeal, http://www.atsociety.org.uk/ See also: Apoptosis; Cancer Susceptibility; Double-Strand Break Repair Model; Leukemia ATP (Adenosine Triphosphate) J Parker Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0085 Adenosine triphosphate (ATP) is the primary chemical energy source used by cells to carry out energy- requiring reactions. Adenosine is a nucleoside in which the purine base adenine is covalently linked to the 1 0 carbon of the sugar ribose. In the case of ATP, three phosphate groups are also present, bonded to the 5 0 carbon of the ribose; therefore the ATP used by cells is adenosine 5 0 -triphosphate. The bond connecting the first phosphate group to the carbon is a phosphoester bond, and the bonds between the phosphate groups are phosphoanhydride bonds (formerly called phos- phodiester bonds). These latter two bonds are often referred to as `high energy' bonds because con- siderable free energy, about 30.5 kJ per mole, is ATP (Adenosine Triphosphate) 115

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Encyclopedia of Genetics || ATP (Adenosine Triphosphate)