Two proteins act as molecular tailors in DNA repair

November 13, 2009

( -- On average, our cells encounter a very lethal form of DNA damage 10 times a day. Lucky for us, we have the capacity to repair each and every one of them. New research now reveals exactly how two well-known proteins are involved in the process, a finding that not only helps shed light on cancer but also on how our cells maintain the integrity of our genome.

Every day tiny segments of our DNA are chipped or fragmented or get stuck together when they should really be pulled apart. But what our necessarily lacks in stability it makes up for with a phalanx of guards that monitor and repair the damage.

In new research to appear in this week’s advance online issue of Science, researchers at Rockefeller University and Harvard Medical School have pinpointed the role that two well-known proteins play in the repair of one of the most lethal types of . The damage, known as inter-strand crosslinks, occurs when the two strands of the are linked together, blocking and transcription.

“Our cells encounter, on average, 10 inter-strand crosslinks a day,” says Agata Smogorzewska, head of the Laboratory of Genome Maintenance at Rockefeller University. “We suspected that these two proteins directly participated in the repair process. Until now, we knew that they localized to the sites of damage but we had no idea what they were doing there. This work breaks that barrier.“

The two proteins, called FANCI and FANCD2, are part of the Fanconi pathway, which repairs inter-strand crosslinks. If any one of the 13 proteins in this pathway is damaged, the result is Fanconi anemia, a that leads to failure and leukemia, among other cancers, as well as many physiological defects.

In 2007, when Smogorzewska discovered FANCI, it was shown that the protein formed a complex with FANCD2, which is then chemically altered through a process called ubiquitylation. The chemically altered complex is then recruited to the site of the crosslink, where it joins forces with other repair molecules. Beyond these details, the researchers knew that repair involves snipping out and replacing the damaged DNA, but didn’t know if FANCI and FANCD2 play a role in this molecular tailoring.

Using a specialized cell system of frog egg extracts, the researchers found that the two proteins are essential in the excision and insertion steps, providing powerful evidence that Fanconi anemia is a bona fide repair disorder, explains Smogorzewska. The finding also explains why cells taken from Fanconi anemia patients die when exposed to inter-strand crosslink-inducing agents such as chemotherapy drugs.

“The beauty of this work is that we now have a system that enables us to explore the behavior of other key proteins in Fanconi anemia and form a picture of how they all work together,” says Smogorzewska. “This will not only help shed light on how to fight but how to maintain the stability of our genome.”

More information: Science online: November 12, 2009, The Fanconi Anemia Pathway Promotes Replication-Dependent DNA Interstrand Cross-Link Repair, Puck Knipscheer, Markus Räschle, Agata Smogorzewska, Milica Enoiu, The Vinh Ho, Orlando D. Schärer, Stephen J. Elledge and Johannes C. Walter

Provided by Rockefeller University (news : web)

Related Stories

Recommended for you

A metabolic switch to turn off obesity

October 27, 2016

You've tried all the diets. No matter: you've still regained the weight you lost, even though you ate well and you exercised regularly! This may be due to a particular enzyme in the brain: the alpha/beta hydrolase domain-6 ...

Natural compound reduces signs of aging in healthy mice

October 27, 2016

Much of human health hinges on how well the body manufactures and uses energy. For reasons that remain unclear, cells' ability to produce energy declines with age, prompting scientists to suspect that the steady loss of efficiency ...

Scientists develop 'world-first' 3-D mammary gland model

October 27, 2016

A team of researchers from Cardiff University and Monash Biomedicine Discovery Institute has succeeded in creating a three-dimensional mammary gland model that will pave the way for a better understanding of the mechanisms ...

Mitochondria control stem cell fate

October 27, 2016

What happens in intestinal epithelial cells during a chronic illness? Basic research conducted at the Chair of Nutrition and Immunology at the Technical University of Munich (TUM) addressed this question by generating a new ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.