Pathogenesis of ataxia-telangiectasia: the next generation of ATM functions

Abstract

In 1988, the gene responsible for the autosomal recessive disease ataxia- telangiectasia (A-T) was localized to 11q22.3-23.1. It was eventually cloned in 1995. Many independent laboratories have since demonstrated that in replicating cells, ataxia telangiectasia mutated (ATM) is predominantly a nuclear protein that is involved in the early recognition and response to double-stranded DNA breaks. ATM is a high-molecular-weight PI3K-family kinase. ATM also plays many important cytoplasmic roles where it phosphorylates hundreds of protein substrates that activate and coordinate cell-signaling pathways involved in cell-cycle checkpoints, nuclear localization, gene transcription and expression, the response to oxidative stress, apoptosis, nonsense-mediated decay, and others. Appreciating these roles helps to provide new insights into the diverse clinical phenotypes exhibited by A-T patients-children and adults alike-which include neurodegeneration, high cancer risk, adverse reactions to radiation and chemotherapy, pulmonary failure, immunodeficiency, glucose transporter aberrations, insulin-resistant diabetogenic responses, and distinct chromosomal and chromatin changes. An exciting recent development is the ATM-dependent pathology encountered in mitochondria, leading to inefficient respiration and energy metabolism and the excessive generation of free radicals that themselves create life-threatening DNA lesions that must be repaired within minutes to minimize individual cell losses.

Figure 1

ATM kinase signals to diverse metabolic pathways in the cytoplasm. During in vitro experiments, oxidants/prooxidants induce the phosphorylation and activation of ATM dimers that appear to be linked via intermolecular disulfide bonds formed at a conserved C2991 residue in the C- terminus. It remains to be fully clarified whether these ATM dimers are similarly activated in response to endogenously generated ROS—acting directly on ATM, or else via the platelet-derived growth factor receptor β—and are responsible for regulating (1) expression of mTORC1; (2) synthesis of reduced glutathione (GSH) via the PPP; and (3) insulin-induced protein synthesis in response to oxidative stress. Nevertheless, the activation of ATM in response to oxidative stress leads to the inhibition of mTORC1 activity via the LKB1/AMPK/TSC2 signaling cascade. Activated ATM phosphorylates LKB1 (Thr366), which in turn phosphorylates AMPK (Thr172). AMPK subsequently phosphorylates TSC2 (Thr1271, Ser1387), which inhibits the expression of mTORC1, thereby promoting autophagy.^- Furthermore, ATM regulates TSC2 activity in response to hypoxia by directly phosphorylating HIF1α (Ser696), and hence blocks mTORC1 activity. In addition, activated ATM induces complex formation between glucose-6-phosphate dehydrogenase (G6PD) and Hsp27, which increases the production of NADPH via the PPP, resulting in elevated intracellular levels of the antioxidant glutathione. Cytoplasmic ATM also regulates protein synthesis in response to insulin by phosphorylating 4E-BP1 (Ser111) and enhancing mRNA translation. Moreover, ATM phosphorylates Akt (Ser473) in response to insulin, which stimulates the translocation of the glucose transporter 4 (GLUT4) complex into the cell membrane via an as yet undetermined mechanism.^,

Figure 2

XCIND syndrome disorders and associated DNA-repair pathways. The prototype for the XCIND syndrome is A-T, involving X-ray sensitivity, Cancer susceptibility, Immunodeficiency, Neurologic involvement, and DSB repair. The NMR complex is necessary for recruitment of ATM to a DSB and activation of its kinase activity. Patients lacking NBS (nibrin), Mre11 (aka ATLD), and Rad50 proteins are usually children with features of XCIND syndrome, although the types of neurologic involvement differ for the 3 disorders.^, Nonhomologous end-joining (NHEJ) repair comprises the major DSB repair pathway in man. Patients lacking functional proteins in this pathway often present in infancy as SCID, although DNA ligase IV deficiency has been described as well in children with primary dwarfism and in adults.^, PNKP protein has both polynucleotide kinase and phosphatase functions, moving the phosphate groups from 5′ to 3′, thereby optimizing conditions for ligation in end-joining. PNKP may also play a role in single-strand break repair. Affected infants display intractable seizures, microcephaly, and developmental delay. Absence of RNF168 protein results in poor retention of 53BP1 and BRCA1 at sites of DSB, as well as at other predicted interactions within the chromatin ubiquitin ligase cascade (CULC). Two patients with RNF168 have been described, both with adult-onset immunodeficiency, neurologic involvement, and growth retardation^,,; severe microcephaly was noted in 1, with normal intelligence. The inclusion of Fanconi anemia (itself a syndrome) within this partial list of XCIND syndrome-associated disorders is based arguably on the manifestations of radiosensitivity, and many of the patients have also been associated with untoward responses to chemotherapy. The disorders listed herein are inherited as autosomal recessives.