Chaperone enzyme provides new target for cancer treatments

Chaperone enzyme provides new target for cancer treatments

UNC scientists who study how cells repair damage from environmental factors like sunlight and cigarette smoke have discovered how a "chaperone" enzyme plays a key role in cells' ability to tolerate the DNA damage that leads to cancer and other diseases.

The enzyme, known as Rad18, detects a protein called DNA polymerase eta (Pol eta) and accompanies it to the sites of sunlight-induced DNA damage, enabling accurate repair. When Pol eta is not present, alternative error-prone polymerases take its place – a process that leads to DNA mutations often found in cancer cells.

In one known example, faulty DNA repair due to Pol eta- deficiency is responsible for the genetic disease xeroderma pigmentosum-variant, which makes patients extremely susceptible to skin cancers caused by exposure to sunlight. However, scientists did not know how the cells selected the correct DNA Polymerase for error-free repair of each type of DNA damage.

"We found that the mechanism that promotes the 'chaperone' enzyme to recruit Pol eta to sites of DNA damage is managed by another signaling protein termed 'Cdc7' which we know is essential to normal regulation of the cellular lifecycle," said lead author Cyrus Vaziri, PhD, who is an associate professor of pathology and laboratory medicine and member of UNC Lineberger Comprehensive Cancer Center. Thus cells employ Cdc7 to ensure accurate DNA repair during the stage of their lifecycle that is most vulnerable to cancer-causing mutations.

The study was published in November in the Journal of Cell Biology.

According to Vaziri, the dual role that Cdc7 plays in the cell lifecycle and DNA repair offers a promising target for potential cancer therapies.

"We know that cancer cells have high levels of Cdc7 activity and can evade some DNA-damaging therapies such as cis-Platinum through Rad18 and Pol eta activity. We may be able to target this pathway in platinum-resistant tumors to prevent DNA repair and enhance cancer cell killing by platinating agents," he said.

Skin provides Australia's first adult stem cells for rare genetic disease

Skin provides Australia's first adult stem cells for rare genetic disease

(PhysOrg.com) -- Scientists have developed Australia’s first adult induced pluripotent stem cell lines using skin biopsies from patients with the rare genetic disease Friedreich Ataxia (FA).

The study was conducted by the University of Melbourne and Monash Institute of Medical Research and is published in the current online edition of the international journal Stem Cell Reviews and Reports. It is the first time adult pluripotent stem cells, known as iPS cells have been developed for a specific disease in Australia, allowing for the development of new treatments for FA and related conditions such as diabetes and heart disease.

Induced pluripotent stem (iPS) cells result from the reprogramming of adult cells, such as skin cells, and are similar to embryonic stem cells in that they have the potential to generate any cell type of the body.

Dr Alice Pébay and Dr Mirella Dottori, co leaders of the study from University of Melbourne, characterized and directed the Friedreich Ataxia iPS cells to become specific cell types, including heart cells and nerves, which are normally not functioning well in the disease.
“By focusing on the heart and nerve cell types, we hope to be able to develop treatments to improve heart function and the loss of movement experienced by patients with FA,” Dr Pébay said.

Friedreich Ataxia affects one in 30,000 people globally, and Dr Paul Verma of the Monash Institute of Medical Research said this research could be applied to other diseases.

“Due to the number of symptoms experienced by people with FA, including diabetes and heart disease, this resource could be applied to developing treatment for those conditions and helping even more people, “ he said.

Dr Dottori said the research could not have been achieved without a significant network of experts and support from the Friedreich Ataxia Research Association (Australasia) (FARA-A) and the Friedreich Ataxia Research Alliance (FARA) in the United States.

“It is the collective effort of clinicians, scientists, patients and FARA that has made this discovery possible,” she said.

Ms Varlli Beetham, Executive Director of FARA said the finding provided real hope for people suffering the debilitating condition. “We are proud to have supported this research effort and look forward to the next stage of research, the development of new trial treatments,” she said.