The closer

By Edyta Zielinska The closer Dr. Pablo Huertas / Steve Jackson lab / The Wellcome Trust/Cancer Research UK Gurdon Institute The paper: A. Sartori et al., “Human CtIP promotes DNA end resection,” Nature, 450:509–14, 2007. (Cited 135 times) The finding: Stephen Jackson and colleagues at the University of Cambridge, United Kingdom, showed that the protein CtIP, known to interact with tumor suppressor genes, could

Edyta Zielinska
Apr 1, 2010

The closer

Dr. Pablo Huertas / Steve Jackson lab / The Wellcome Trust/Cancer Research UK Gurdon Institute

The paper:
A. Sartori et al., “Human CtIP promotes DNA end resection,” Nature, 450:509–14, 2007. (Cited 135 times)

The finding:
Stephen Jackson and colleagues at the University of Cambridge, United Kingdom, showed that the protein CtIP, known to interact with tumor suppressor genes, could also help repair DNA double-strand breaks by homologous recombination, which uses the duplicate, unbroken chromosome as a template. A better understanding of the repair pathway can potentially lead to new targets for cancer, characterized by a flawed repair system.

The detail:
The researchers knew that CtIP binds to another protein involved in homologous repair. When they would “zap [the cells] with a laser” to create double-strand breaks, says Jackson, they’d see CtIP—bound to GFP—light up at the damage site. This occurred only in S phase or G2, when...

The follow up:
While investigating how cells choose between repair pathways, Jackson’s group discovered that cyclin-dependent kinases (CDKs), which accumulate as the cell cycle progresses, would bind to CtIP when CDK numbers were abundant in S or G2, triggering the protein’s homologous repair activity (J Biol Chem, 284:9558–65, 2009).

The nuance:
A group led by Kevin Hiom from Dundee University also found last year that CtIP only performed the more faithful, homologous repair if both CDKs and the BRCA1 gene product were present in the cell. “BRCA1 mediates the switch to homologous recombination,” says Hiom.

Steps of homologous recombination:
1. Chewing back 5´ to 3´ on two of the four strands
2. Search for homology on sister chromatid and binding the 3´ single-strand overhangs
3. DNA synthesis and strand ligation

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