A genetic screen identifies the Triple T complex required for DNA damage signaling and ATM and ATR stability.

Article Details

Citation

Hurov KE, Cotta-Ramusino C, Elledge SJ

A genetic screen identifies the Triple T complex required for DNA damage signaling and ATM and ATR stability.

Genes Dev. 2010 Sep 1;24(17):1939-50. doi: 10.1101/gad.1934210.

PubMed ID
20810650 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
DNA-dependent protein kinase catalytic subunitP78527Details
Serine/threonine-protein kinase mTORP42345Details
Serine-protein kinase ATMQ13315Details
Serine/threonine-protein kinase ATRQ13535Details