ATR Takes ATRIP to Fix Defects: Protein partners watch over the genome (DNA damage)
Authors: Davenport R. John 
Published: August 2003

In eukaryotic cells, protein sentries ensure that the genome is complete before cell division proceeds. When DNA is damaged or its replication machinery conks out, the genome guardians attach phosphate groups to other proteins; this chemical addition triggers these proteins to bring the cell cycle to a halt and activate DNA repair machinery. A breakdown in this system can impair health: People with a defective copy of the gene for one of those proteins--called
ATM
--suffer from a disorder known as ataxia telangiectasia (see Transgenic Mouse Entries:
tg1
,
tg2
, and
tg3
). Symptoms of the disorder include neuronal degeneration, weakened immunity, and increased risk of cancer. Although scientists know a fair amount about ATM, key information is missing about the activities of a related protein--ATR--that also is thought to play a crucial role in the process by which the cell maintains an intact genome. ATR is difficult to study because cells or animals that have been engineered to lack the protein die. Researchers have now identified an ATR sidekick: probably one of the proteins it prods into action by adding a phosphate group.

To isolate protein partners of ATR, Cortez and colleagues pulled ATR from a soup of human embryonic kidney cell contents using antibodies as a hook; a phosphorylated protein that they named ATRIP came along for the ride. ATRIP appears to be a substrate of ATR: ATR adds phosphate to ATRIP in the test tube. When the team treated cells with DNA-damaging chemicals or radiation, ATR and ATRIP--which are normally dispersed throughout the nucleus--congregated at particular spots. Previous work on ATR suggests that those sites might be points of mayhem caused by blocked DNA replication machinery. Moreover, additional experiments indicate that ATRIP enhances the ability of cells to recognize DNA damage: After exposure to radiation, cells with abnormally small amounts of ATRIP were twice as likely as normal ones to proceed with the cell cycle rather than stop to address the problem. Together, the results suggest that ATR phosphorylates ATRIP and that the two proteins help the cell deal with DNA damage.

It remains uncertain which types of chromosomal wreckage ATR recognizes. Earlier work suggested that ATR senses trouble with DNA replication. The new study hints that ATR in partnership with ATRIP might also spot double-strand breaks, because ATRIP helps the cell respond appropriately to radiation, which severs DNA to produce that type of lesion.

ATRIP resembles two yeast proteins--
RAD26
and DDC2--and might perform similar functions. These proteins bind to the yeast version of ATR, which then activates the two proteins by attaching a phosphate group to them. RAD26 appears to monitor genome integrity, but no one has yet found the corresponding protein in mammalian systems. If future experiments confirm that ATRIP is the counterpart to RAD26, the picture of how animals guard the integrity of the genome will sharpen significantly. The identification of these players will aid investigations that probe how ATR and ATM discern chromosomal abnormalities and set cellular contingency plans in motion--and how defects in the system can lead to disease.

--R. John Davenport

D. Cortez, S. Guntuku, J. Qin, S. J. Elledge, ATR and ATRIP: Partners in checkpoint signaling.
Science
294
, 1713-1716 (2001).
[Abstract/Full Text]