ATM (Ataxia Telangiectasia Mutated Protein) belongs to a family of Kinases that have sequence homology to PI3K (Phosphoinositide 3-Kinase). ATM is a key regulator of multiple signaling cascades which respond to DNA strand breaks induced by damaging agents IR (Ionizing Radiation), radiometric agents or by normal processes. These responses involve the activation of cell cycle Chk factors (Checkpoints factors), DNA repair and Apoptosis. In addition, ATM appears to function as a 'caretaker', suppressing tumorigenesis in specific T cell lineages. Its downstream targets include Chk1 (Cell Cycle Checkpoint Kinase-1), Chk2 (Cell Cycle Checkpoint Kinase-2), tumor suppressors like p53 and BRCA (Breast Cancer), DNA repair factors like Rad50, Rad51, GADD45 (Growth Arrest and DNA-Damage-inducible), and other signaling molecules like c-Abl and NF-KappaB (Nuclear Factor-Kappa B) (Ref.1). In non-irradiated cells ATM exists as a dimer, is not phosphorylated and is present throughout the nucleus. After irradiation, which leads to formation of DNA DSBs (DNA Double Strand Breaks), ATM becomes a monomer, it is phosphorylated on Ser1981 and some pool of it is present at sites of DNA DSBs. ATM monitors the presence of DNA DSBs indirectly, through DNA DSB-induced changes in chromatin structure. ATM is activated by the MRE11 (Meiotic Recombination-11)–Rad50–NBS1 (Nijmegen Breakage Syndrome-1) complex or 53BP1. The former is thought to be recruited at the DSB, whereas the latter is recruited at chromatin regions flanking the DNA DSB and extending up to a few megabases from the DSB. ATM phosphorylates NBS1 on several residues in response to DNA damage and a functional MRE11/Rad50/NBS1 complex is required for Chk2 activation. This links the MRE11/Rad50/NBS1 complex to DNA damage recognition. ATM activated at sites of DNA DSBs may also phosphorylate and activate ATM in the nucleoplasm (Ref.1 & 2). References 1.Exclusion/confirmation of Ataxia-telangiectasia via cell-cycle testing. Heinrich T, Prowald C, Friedl R, Gottwald B, Kalb R, Neveling K, Herterich S, Hoehn H, Schindler D. Eur J Pediatr. 2006 Jan 13;:1-8 [Epub ahead of print] Zgheib O, Huyen Y, DiTullio RA Jr, Snyder A, Venere M, Stavridi ES, Halazonetis TD. Radiother Oncol. 2005 Aug;76(2):119-22. 3.DNA damage regulates CHK2 association with chromatin. Li J, Stern DF. J Biol Chem. 2005 Sep 8; [Epub ahead of print] 4.ATM-mediated phosphorylations inhibit Mdmx/Mdm2 stabilization by HAUSP in favor of p53 activation. Meulmeester E, Pereg Y, Shiloh Y, Jochemsen AG. Cell Cycle. 2005 Sep;4(9):1166-70. Epub 2005 Sep 29. 5.Defective ATM-p53-mediated apoptotic pathway in multiple sclerosis. Deng X, Ljunggren-Rose A, Maas K, Sriram S. Ann Neurol. 2005 Oct;58(4):577-84. 6.ATM-dependent phosphorylation of ATF2 is required for the DNA damage response. Bhoumik A, Takahashi S, Breitweiser W, Shiloh Y, Jones N, Ronai Z. Mol Cell. 2005 May 27;18(5):577-87. Krause DR, Jonnalagadda JC, Gatei MH, Sillje HH, Zhou BB, Nigg EA, Khanna K. Oncogene. 2003 Sep 4;22(38):5927-37. 8.Direct regulation of CREB transcriptional activity by ATM in response to genotoxic stress. Shi Y, Venkataraman SL, Dodson GE, Mabb AM, LeBlanc S, Tibbetts RS. Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):5898-903. Epub 2004 Apr 8. 9.Proapoptotic BID is an ATM effector in the DNA-damage response. Kamer I, Sarig R, Zaltsman Y, Niv H, Oberkovitz G, Regev L, Haimovich G, Lerenthal Y, Marcellus RC, Gross A. Cell. 2005 Aug 26;122(4):593-603. 10.ATM and ataxia telangiectasia. McKinnon PJ. EMBO Rep. 2004 Aug;5(8):772-6. Review. |