title: A genetic screen identifies the Triple T complex required for DNA damage signaling and ATM and ATR stability.
abstract: In response to DNA damage, cells activate a complex signal transduction network called the DNA damage response (DDR). To enhance our current understanding of the DDR network, we performed a genome-wide RNAi screen to identify genes required for resistance to ionizing radiation (IR). Along with a number of known DDR genes, we discovered a large set of novel genes whose depletion leads to cellular sensitivity to IR. Here we describe TTI1 (Tel two-interacting protein 1) and TTI2 as highly conserved regulators of the DDR in mammals. TTI1 and TTI2 protect cells from spontaneous DNA damage, and are required for the establishment of the intra-S and G2/M checkpoints. TTI1 and TTI2 exist in multiple complexes, including a 2-MDa complex with TEL2 (telomere maintenance 2), called the Triple T complex, and phosphoinositide-3-kinase-related protein kinases (PIKKs) such as ataxia telangiectasia-mutated (ATM). The components of the TTT complex are mutually dependent on each other, and act as critical regulators of PIKK abundance and checkpoint signaling.
authors.affiliation: Howard Hughes Medical Institute and Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Hurov
authors.forename: Cecilia
authors.initials: C
authors.lastname: Cotta-Ramusino
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Elledge
mesh_terms: D019870:1-Phosphatidylinositol 4-Kinase / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018816:Genes, cdc; D055106:Genome-Wide Association Study; D006801:Humans; D007259:Infrared Rays; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D055550:Protein Stability; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C409823:ETV7 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D050783:Proto-Oncogene Proteins c-ets; C552070:TTI2 protein, human; C551530:Tti1 protein, human; D025521:Tumor Suppressor Proteins; D019870:1-Phosphatidylinositol 4-Kinase; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases
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