Unknotting DNA clue to cancer syndrome

August 3, 2007
Spaghetti Junctions
Multichromosome Holliday junctions, modeled with spaghetti. Twisted spaghetti strands represen t DNA strands that have crossed multiple times. Such multiple crossovers were seen in yeast with a nonfunctioning SGS1 gene. Credit: Neil Hunter, UC Davis

A new UC Davis study that explains the actions of a gene mutation that causes early onset cancer provides a fundamental insight into the mechanism of DNA-break repair.

People with Bloom's syndrome, a rare genetic disease, typically develop cancer in their twenties. The underlying cause is a mutation in a gene called Blm, which encodes a member of the RecQ family of DNA-unwinding enzymes, or helicases, that are involved in repairing DNA.

Neil Hunter, assistant professor of microbiology at UC Davis, and his colleagues studied the equivalent protein in yeast, SGS1. They found that when SGS1 was defective, yeast chromosomes became more promiscuous in combining with each other as they attempt to repair breaks in the DNA.

Normally, to repair broken DNA, matching chromosomes associate so that an intact chromosome can act as a template for the damaged one. The DNA strands are then exchanged to form four-way structures called Holliday junctions. To complete repair, these junctions are resolved in one of two ways: either leaving the original chromosomes intact, or exchanging the chromosome arms to form a crossover.

Both yeast and human cells contain two copies of each chromosome, one from each parent. During the cell division cycle, each chromosome gets copied, so for a while there are four of each.

Textbook models show only one end of a DNA break exchanging strands with the template chromosome, while the other end waits passively, Hunter said. But the new study clearly shows that both break ends can autonomously fish around to capture repair templates. Furthermore, when SGS1 is defective, all four matching chromosomes present can get entangled in a multichromosome Holliday junction.

"It's a lot less tidy than we thought, but with both break ends being capable of exchange the repair process will also be more efficient. The drawback is that it's also more risky," Hunter said.

Resolution of multichromosome Holliday junctions increases the risk of rearranging chromosomes, with chunks of DNA ending up in the wrong place. Such rearrangements can lead to cancer. In their normal forms, the SGS1 and Bloom's proteins keep the situation under control by separating the entangled chromosomes and preventing undesirable crossovers.

While these experiments were done in yeast, Hunter predicted that the results could be extended to human cells.

"This is a fundamental insight into the mechanism of DNA-break repair," he said.

Citation: The paper is published in the July 27 issue of the journal Cell. The other authors are Steve D. Oh, Jessica P. Lao, Patty Yi-Hwa Hwang, all graduate students at UC Davis, and Andrew F. Taylor and Gerald R. Smith at the Fred Hutchinson Cancer Research Center in Seattle.

Source: University of California - Davis

Explore further: Insights into genomic instability during the early stages of embryonic cell development

Related Stories

Extra support for cells under stress may be a job for DoGs

July 17, 2015

Stress wreaks havoc on our health—even at the cellular level. Cells under certain kinds of duress can lose water and put pressure on our DNA, making it difficult for genes to carry out critical functions such as self-repair. ...

Forks colliding: How DNA breaks during re-replication

June 4, 2015

Leveraging a novel system designed to examine the double-strand DNA breaks that occur as a consequence of gene amplification during DNA replication, Whitehead Institute scientists are bringing new clarity to the causes of ...

Study shows where damaged DNA goes for repair

May 3, 2015

A Tufts University study sheds new light on the process by which DNA repair occurs within the cell. In research published in the May 15 edition of the journal Genes & Development and available May 4 online in advance of print, ...

Recommended for you

Machine Translates Thoughts into Speech in Real Time

December 21, 2009

(PhysOrg.com) -- By implanting an electrode into the brain of a person with locked-in syndrome, scientists have demonstrated how to wirelessly transmit neural signals to a speech synthesizer. The "thought-to-speech" process ...

Quantum Theory May Explain Wishful Thinking

April 14, 2009

(PhysOrg.com) -- Humans don’t always make the most rational decisions. As studies have shown, even when logic and reasoning point in one direction, sometimes we chose the opposite route, motivated by personal bias or simply ...

Why do the majority of people never get cancer?

January 22, 2009

(PhysOrg.com) -- Every year, millions of people are diagnosed with cancer - a remarkably high number. But what about the flipside of those statistics? That is, two out of three people never get cancer, and more than half ...

0 comments

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.