Protein-Protein Interactions in Ataxia Telangiectasia | 10

ABSTRACT

A taxia telangiectasia (AT) is an early-onset genetic disorder characterized by progressive neurondegeneration, chromosome instability and an extreme sensitivity to DNA damaging agents such as ionizing radiation.1'3 An autosomal recessive disorder, AT occurs in approximately 1 out of40,000 births in the United States. However this frequency varies dramati cally around the world. AT patients appear normal at birth but by age 2-3 years the disease starts showing the signs and by age 10 complete loss ofwalking occurs.13 MRI analysis of the cerebellum shows cerebellar atrophy by age 10 and a defect in the differentiation and maturation of Purkinje cells. Additional symptoms appear as the disease progresses including oculocutaneous telangiectasias (spidery veins in the eyes), oculomotor apraxia, dysarthria, immunodeficiency, as well as a predisposition to cancer, particularly lymphoid cancers. At present there is no treatment for AT, though patients do receive therapy for secondary effects of the disease. Death occurs frequently during the teenage years and is generally attributed to early-onset incurable cancers or infection due to immunodeficiency.1'3

AT is the result of defects in the gene encoding the protein Ataxia telangiectasia-mutated (ATM), a member of the phosphatidylinositol 3-kinase-related protein kinase (PIKK) family. W hile a variety of mutations in th e ATM gene are identified in patients, the overall effect is a loss of ATM protein kinase activity.1,4 The PIKK kinases belong to the conserved family of serine/ threonine protein kinases that contain a domain typical of the lipid kinase phosphatidylinositol 3-kinase (PI3K).5 The mammalian PIKK family includes five protein kinases: ATM, ATM-and Rad3-related (ATR), hSMG-1, the mammalian target of rapamycin, mTOR (also termed FRAP) and the catalytic subunit o f the DNA-dependent protein kinase (DNA-PKcs). A sixth member, transformation/transcription domain-associated protein (TRRAP), is part of the histone acetyltransferase complex and required for Myc-dependent oncogenesis but has no protein kinase activity.3,5,6

As part of cellular DNA damage responses, PIKK kinases initiate damage signaling cascades that serve to arrest cell cycle progression and promote DNA damage repair by phosphorylating many downstream substrates such as C h k l, Chk2 and p53. ATM and DNA-PKcs primarily respond to DNA double strand breaks (DSBs) while ATR mainly responds to damages generated by UV exposure and other nonDSB DNA damage. However, both ATR and hSMG-1 have been also found to respond to DSBs, although much slower than ATM and ATR activity has been found to be at least partially dependent on ATM. As a central player in cellular responses to DNA damage, ATM and related kinases function through avast protein-protein interaction network.3,5'12 A recent study