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PMID:20810650

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Citation

Hurov, KE, Cotta-Ramusino, C and Elledge, SJ (2010) A genetic screen identifies the Triple T complex required for DNA damage signaling and ATM and ATR stability. Genes Dev. 24:1939-50

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.

Links

PubMed PMC2932975 Online version:10.1101/gad.1934210

Keywords

1-Phosphatidylinositol 4-Kinase/metabolism; Carrier Proteins/genetics; Carrier Proteins/metabolism; Cell Cycle/genetics; Cell Cycle Proteins/metabolism; Cell Line; Cell Line, Tumor; DNA Damage/radiation effects; DNA-Binding Proteins/metabolism; Genes, cdc; Genome-Wide Association Study; Humans; Infrared Rays; Molecular Chaperones; Protein Stability; Protein-Serine-Threonine Kinases/metabolism; Proto-Oncogene Proteins c-ets/genetics; Proto-Oncogene Proteins c-ets/metabolism; RNA Interference; Signal Transduction; Tumor Suppressor Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:TTI1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13315

F

Seeded From UniProt

complete

HUMAN:TTI1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13535

F

Seeded From UniProt

complete

HUMAN:TTI1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9Y4R8

F

Seeded From UniProt

complete

HUMAN:TTI1

involved_in

GO:0050821: protein stabilization

ECO:0005547: biological system reconstruction evidence based on inference from background scientific knowledge used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TTI1

located_in

GO:0005634: nucleus

ECO:0005547: biological system reconstruction evidence based on inference from background scientific knowledge used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TTI1

involved_in

GO:2000003: positive regulation of DNA damage checkpoint

ECO:0005547: biological system reconstruction evidence based on inference from background scientific knowledge used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TTI1

located_in

GO:0110078: TTT complex

ECO:0000353: physical interaction evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ATM

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O43156

F

Seeded From UniProt

complete

HUMAN:ATR

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O43156

F

Seeded From UniProt

complete

HUMAN:TTI2

involved_in

GO:0050821: protein stabilization

ECO:0005547: biological system reconstruction evidence based on inference from background scientific knowledge used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TTI2

located_in

GO:0005634: nucleus

ECO:0005547: biological system reconstruction evidence based on inference from background scientific knowledge used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TTI2

involved_in

GO:2000003: positive regulation of DNA damage checkpoint

ECO:0005547: biological system reconstruction evidence based on inference from background scientific knowledge used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TTI2

located_in

GO:0110078: TTT complex

ECO:0000353: physical interaction evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TELO2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O43156

F

Seeded From UniProt

complete

HUMAN:TELO2

involved_in

GO:0050821: protein stabilization

ECO:0005547: biological system reconstruction evidence based on inference from background scientific knowledge used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TELO2

located_in

GO:0005634: nucleus

ECO:0005547: biological system reconstruction evidence based on inference from background scientific knowledge used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TELO2

involved_in

GO:2000003: positive regulation of DNA damage checkpoint

ECO:0005547: biological system reconstruction evidence based on inference from background scientific knowledge used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TELO2

located_in

GO:0110078: TTT complex

ECO:0000353: physical interaction evidence used in manual assertion

C

Seeded From UniProt

complete

See also

References

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