New way found by which metabolism is linked to the regulation of DNA

Jul 03, 2014

A research team at the Faculty of Medicine & Dentistry at the University of Alberta have discovered a new way by which metabolism is linked to the regulation of DNA, the basis of our genetic code. The findings may have important implications for the understanding of many common diseases, including cancer.

The DNA wraps around specialized proteins called histones in the cell's . Normally, histones keep the DNA tightly packaged, preventing the expression of genes and the replication of DNA, which are required for cell growth and division. In order for these critical functions to take place, histones need to be modified with the attachment of an acetyl-group, donated by a critical molecule called acetyl-CoA. This attachment relaxes the DNA, allowing for DNA replication and gene expression. This mechanism is called "epigenetic regulation of DNA" and is important for normal functions (like the growth of an embryo or brain functions) or in common diseases like heart failure or cancer. Until now, how the nucleus generates acetyl-CoA for histone acetylation had remained elusive.

The research team, lead by postdoctoral fellow Gopinath Sutendra and professor Evangelos Michelakis in the Department of Medicine, discovered that an enzyme thought to reside only within , called Pyruvate Dehydrogenase Complex (PDC), can actually find its way into the nucleus and do what it is designed to do in the mitochondria: generate acetyl-CoA. When in mitochondria, PDC uses the carbohydrates from our diet to generate acetyl-CoA for energy production. When in the nucleus, PDC can produce acetyl-CoA for histone acetylation.

"Although this jumping of an enzyme from one organelle into another in the cell is not unheard off, our results were quite surprising", Sutendra says. "We wanted to measure acetyl-CoA levels and PDC in the mitochondria because that's where we thought they were. But accidentally we had the nuclei isolated at the same time and we saw PDC in the nucleus. So we asked, 'what is PDC doing there?' And that started it all."

"We were surprised that, despite the recognized importance of histone acetylation in cell biology and , and despite the efforts by many to develop drugs that regulate histone acetylation, the source of acetyl-CoA in the nucleus had remained unknown," Michelakis says. "Sometimes the answers to important biological questions are just next to you, waiting to be discovered," he adds.

The team found that the translocation of PDC into the nucleus made cancer cells grow faster, an observation that may lead to additional strategies in the war against cancer. Yet, because the findings relate to how our DNA is regulated in general, this work may have far broader implications for many physiologic or pathologic conditions where epigenetic regulation is critical. "We are very excited about this new pathway linking energy production (the process known as metabolism) with gene regulation," the researchers say.

The work is published in the July 3, 2014, issue of the journal Cell. Michelakis is particularly proud of the fact that this is the product of a team that is entirely based at the University of Alberta. Many young researchers in the Department of Medicine like Adam Kinnaird, Peter Dromparis and Roxane Paulin were critical members of the team that also included technicians (Trevor Stenson, Alois Haromy, Kyoko Hashimoto) and researchers from the NanoFAB facility (Nancy Zhang, Eric Flaim). The work was funded by the Canadian Institutes for Health Research and the Hecht Foundation (Vancouver, Canada).

Explore further: Protein anchors help keep embryonic development 'just right'

add to favorites email to friend print save as pdf

Related Stories

Molecular switch controls the destiny of self-eating cells

Jul 17, 2013

The study is the result of a collaboration of scientists at Karolinska Institutet in Sweden, University of Michigan, and University of California San Diego, USA, who were interested in finding out whether autophagy can be ...

New control target for cancer metabolism: Acetylation

Feb 06, 2014

(Medical Xpress)—Cancer cells are not interested in sustainability. They gobble up sugar inefficiently, brushing aside their mitochondria, the efficient miniature power plants that supply energy to healthy ...

Recommended for you

DNA may have had humble beginnings as nutrient carrier

16 hours ago

New research intriguingly suggests that DNA, the genetic information carrier for humans and other complex life, might have had a rather humbler origin. In some microbes, a study shows, DNA pulls double duty ...

Central biobank for drug research

16 hours ago

For the development of new drugs it is crucial to work with stem cells, as these allow scientists to study the effects of new active pharmaceutical ingredients. But it has always been difficult to derive ...

User comments : 1

Adjust slider to filter visible comments by rank

Display comments: newest first

JVK
1 / 5 (1) Jul 05, 2014
"In flies, ecological and social niche construction can be linked to molecular-level cause and effect at the cellular and organismal levels via nutrient-dependent changes in mitochondrial tRNA and a nuclear-encoded tRNA synthetase. The enzyme enables attachment of an appropriate amino acid, which facilitates the reaction required for efficient and accurate protein synthesis (Meiklejohn et al., 2013)." -- Excerpted from Nutrient-dependent/pheromone-controlled adaptive evolution: a model http://www.socioa...53/27989

Nutrient-dependent pheromone-controlled amino acid substitutions differentiate the cell types of all individuals in all species from microbes to man via conserved molecular mechanisms. Others seem to just now be realizing this, although it was addressed in the molecular epigenetics section of our 1996 Hormones and Behavior review. http://www.hawaii...ion.html