Yeast protein's attributes may explain tumor-suppressing work of human counterpart

Jan. 16, 2014


BLOOMINGTON, Ind. -- An Indiana University biochemist is the lead author on new research identifying two DNA-damaging characteristics in a yeast protein whose human counterpart has been linked to cancer and premature aging.

Using the yeast protein Hrq1 as a model for the human enzyme RecQ4, IU assistant professor Matthew Bochman and a team based out of Princeton University have uncovered two important, yet unrelated, traits in Hrq1 that each promote genetic integrity: The yeast protein protected cells against highly toxic DNA lesions called inter-strand crosslinks and also inhibited an enzyme complex, telomerase, that is activated in about 90 percent of all tumors.

“Very little is known about both human RecQ4 and Hrq1, and both of these activities are rare,” Bochman said of the findings published today in Cell Reports. “But to find both activities co-existing in a single protein is unprecedented.”

Loss of one or both of the tumor-suppressing traits -- promoting inter-strand crosslink repair and suppressing telomerase -- could explain why mutations in human RecQ4 are linked to cancer and aging, he added.

The work found that yeast cells lacking Hrq1, which is among a class of enzymes known as helicases responsible for unwinding and separating an organism’s genes, exhibited two particularly dangerous DNA-damaging characteristics: They were hypersensitive to both DNA inter-strand crosslinks and to telomere addition to DNA breaks.

Telomeres are like the plastic tips on shoelaces and keep chromosome ends from deteriorating and eventually scrambling genetic information, and telomerase is the enzyme assigned with elongating those protective caps. Short telomeres are a hallmark of aging, and overactive telomerase allows cancer cells to multiply uncontrollably, so  proper telomerase activity is crucial for health. The new work found that Hrq1 affected several aspects of telomere biology, including inhibiting telomerase at telomere sites and at locations where lethal breaks in both strands of the DNA double helix had occurred.

In addition to inhibiting telomerase, the researchers also found that Hrq1 promoted genetic integrity by acting catalytically to advance inter-strand crosslink repair, suggesting that Hrq1 cells' strong sensitivity to inter-strand crosslinks may be a first line of defense against the dangerous lesions.

Eventually, Bochman’s lab at IU, including biochemistry graduate student Cody Rogers, wants to determine whether the human RecQ4 protein carries out either or both of the activities that promote genome integrity in Hrq1 yeast cells, and if it does, whether it might explain why RecQ4 mutation results in genomic instability and disease.

“We want to continue exploiting yeast as a simple model to spread our net wide to learn more about Hrq1's genetic and physical interactions in the cell, how Hrq1 inhibits telomerase, when and how it functions during crosslink repair,” he said. “Using yeast is a fast and cost-effective way to perform a lot of experiments and form hypotheses that will ultimately be used to perform very direct experiments in human cell lines on RecQ4.”

Scientists already know that mutations in three of the five human RecQ helicases -- including RecQ4 -- cause Bloom syndrome, Werner syndrome and Rothmund-Thomson syndrome, three disorders associated with an increased predisposition to cancer.

Bochman joined the IU Bloomington College of Arts and Sciences’ Department of Molecular and Cellular Biochemistry in August 2013 after spending four years as a postdoctoral fellow in the Princeton University lab of Virginia A. Zakian, a molecular biologist. Zakian is a co-author on the Cell Reports paper “Hrq1, a homolog of the human RecQ4 helicase, acts catalytically and structurally to promote genome integrity,” with Bochman, Katrin Paeschke of the University of Würzburg (Germany) and Princeton’s Angela Chan. Like Bochman, Paeschke was formerly a postdoctoral fellow in the Zakian lab.