A genetic screen identifies the Triple T complex required for DNA damage signaling and ATM and ATR stability.
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.
Hurov
Kristen E
KE
Howard Hughes Medical Institute and Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Cotta-Ramusino
Cecilia
C
Elledge
Stephen J
SJ
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*
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
Mol Cell. 2009 Aug 14;35(3):384-93
19683501
Nat Rev Mol Cell Biol. 2008 Aug;9(8):616-27
18594563
Development. 2001 Oct;128(20):4045-55
11641227
J Cell Biol. 2009 Oct 5;187(1):25-32
19786574
J Biol Chem. 2009 Aug 28;284(35):23525-31
19605351
J Biol Chem. 2007 Feb 23;282(8):5346-55
17189249
J Biol Chem. 2009 Feb 13;284(7):4140-7
19097996
Genes Dev. 1996 Jun 15;10(12):1491-502
8666233
Chromosoma. 1999 Sep;108(5):278-90
10525964
Nucleic Acids Res. 2007 Jan;35(Database issue):D247-52
17130144
Genes Cells. 2007 Dec;12(12):1357-70
18076573
Genome Res. 2003 Sep;13(9):2129-41
12952881
Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19855-60
18077418
Nat Genet. 2005 Nov;37(11):1281-8
16200065
Science. 2007 May 25;316(5828):1160-6
17525332
J Biol Chem. 2005 Dec 9;280(49):40406-16
16221682
Mol Cell. 2008 Nov 7;32(3):313-24
18995830
Genetics. 1995 Dec;141(4):1351-64
8601479
Curr Biol. 2001 Oct 30;11(21):1706-10
11696330
Nat Genet. 2004 Jun;36(6):636-41
15146185
Genes Dev. 1997 Feb 1;11(3):345-57
9030687
Curr Biol. 2001 Dec 11;11(24):1934-44
11747819
Mol Cell. 2009 Jul 31;35(2):228-39
19647519
J Biol Chem. 2003 Jun 13;278(24):21678-84
12670948
Science. 2008 Feb 1;319(5863):620-4
18239126
Nat Cell Biol. 2007 Apr;9(4):391-401
17384638
Mol Cell Biol. 1996 Jun;16(6):3094-105
8649421
Science. 1998 Dec 4;282(5395):1893-7
9836640
Genes Dev. 2009 Mar 15;23(6):729-39
19261749
Science. 2008 Feb 1;319(5863):617-20
18239125
Cell. 2009 May 29;137(5):835-48
19490893
Proc Natl Acad Sci U S A. 1986 Mar;83(5):1398-402
3513174
J Biol Chem. 2005 Mar 18;280(11):9879-86
15632126
Nature. 2004 Mar 25;428(6981):427-31
15042091
Nat Rev Mol Cell Biol. 2008 Oct;9(10):759-69
18813293
Science. 1996 May 17;272(5264):1010-3
8638122
Cell. 2007 Dec 28;131(7):1248-59
18160036
Genetics. 2005 Dec;171(4):1513-22
16143623
Science. 2005 Feb 18;307(5712):1098-101
15718470
Cell. 2007 Apr 20;129(2):289-301
17412408
Genes Dev. 2004 Sep 1;18(17):2108-19
15342490