Corporate Banner
Satellite Banner
Proteomics
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Changes to DNA On-Off Switches Affect Cells' Ability to Repair Breaks

Published: Wednesday, February 06, 2013
Last Updated: Wednesday, February 06, 2013
Bookmark and Share
Many proteins are involved in everyday DNA repair, but if they are mutated, the repair system breaks down and cancer can occur.

Cells have two complicated ways to repair these breaks, which can affect the stability of the entire genome. Roger A. Greenberg, M.D., Ph.D., associate investigator, Abramson Family Cancer Research Institute and associate professor of Cancer Biology at the Perelman School of Medicine, University of Pennsylvania, together with postdoctoral researcher Jiangbo Tang Ph.D. and colleagues, found a key determinant in the balance between two proteins, BRCA1 and 53BP1, in the DNA repair machinery. Breast and ovarian cancer are associated with a breakdown in the repair systems involving these proteins. Their findings appear in the latest online issue of Nature Structural & Molecular Biology.

The two proteins, BRCA1 and 53BP1, control which of two cell-repair mechanisms will be used: homologous recombination or non-homologous end-joining, technically speaking. This competition has proven to be a key factor in determining whether a cell becomes cancer prone as well as how a cancer cell will respond to chemotherapy.

The key step of the balance is acetylation, the chemical process of adding a compound called an acetyl group to other cellular molecules.

The researchers asked what cell signals determine whether BRCA or 53BP1 predominates at a DNA break site.

DNA in the nucleus is tightly packed around proteins called histones. Acetylation at a specific spot on histone H4 determines the answer. If H4 is acetylated at a specific location, then 53BP1 binding near the broken DNA region is strongly reduced. This leaves BRCA1 free to do the work, kicking in the homologous recombination tool to repair the break.

On the other hand, if acetylation is reduced, 53BP1 outcompetes BRCA1 at a break and the non-homologous end-joining tool repairs the break.

This mechanism can help explain resistance to a promising chemotherapy called PARP inhibition seen in patients and mouse models with BRCA1 mutations. Work from several other research teams surprisingly has shown that if neither BRCA nor 53BP1 are available, then the homologous recombination system goes into action even in the absence of BRCA1 and BRCA1 mutant cancer cells become resistant to PARP inhibitors.

Because of this, Greenberg says, there are some possible applications for making PARP chemotherapy more sensitive: “If you could inhibit specific acetylation events, then a patient’s response to PARP inhibitors might be enhanced by hyperactivating 53BP1 binding to breaks in the context of BRCA1 deficient cancers. What’s more, measuring the levels of acetylation at H4 might predict how responsive an individual is to PARP inhibitors.”

“The story didn’t fall into place the way we thought it would,” says Greenberg. “We didn’t realize that it was a combination of two epigenetic marks that drives the repair system. However, we were able to show that 53BP1 doesn’t bind well to regions of histone H4 that are acetylated at a specific location on H4. Collaboration with Georges Mer, a structural biologist at the Mayo Clinic, helped provide the molecular basis for these findings. We think there will be further complexity to this regulation, creating the possibility for the discovery of additional mechanisms that regulate DNA repair pathways and response to therapy and potential new targets for diagnosis and therapy.”

Co-authors are Nam Woo Cho, Erica M. Manion, Niraj M. Shanbhag, all from Penn, and Gaofeng Cui, Maria Victoria Botuyan, and Georges Mer, from the Department of Biochemistry and Molecular Biology, Mayo Clinic.


Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 3,300+ scientific posters on ePosters
  • More than 4,900+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Study Identifies Potential Treatment Target for Cocaine Addiction
Small change in receptor subunit reduces cocaine seeking in an animal model of addiction.
Thursday, October 30, 2014
Study Confirms No Transmission of Alzheimer's Proteins between Humans
No evidence to show that proteins can spread around within the brain or between animals and humans.
Wednesday, February 06, 2013
Penn-Temple Team Discovers What Keeps a Cell's Energy Source Going
Most healthy cells rely on a complicated process to produce the fuel ATP, understanding it’s production is important for understanding cancers.
Friday, November 30, 2012
Scientific News
Oxygen Can Impair Cancer Immunotherapy
Researchers have identified a mechanism within the lungs where anticancer immune resposnse is inhibited.
Symmetry is Key to Collagen
Researchers describe how symmetry may be the key to growing collagen fibres outside the body.
Breakthrough in GPCR Understanding
Integral Molecular announces breakthrough in understanding the functionality of GPCRs, the largest class of drug targets in human disease.
Designing Ultrasound Tools with Lego-Like Proteins
Study outlines how ultrasound technology can be used for imaging in conjuction with protein engineering.
Enzyme that Triggers Cell Demise in ALS Identified
Scientists from Harvard have identified a key instigator of nerve cell damage in people with amyotrophic lateral sclerosis (ALS).
Molecular Alarm Clock Wakes Resting Ovules
Study of fruit flies yields discovery of a molecular "alarm clock" that activates resting ovules.
Catching Proteins in the Act
Scientists can now observe light activated processes in proteins through the use of free-electron x-ray lasers.
Proteins Preserve Vital Genetic Data
Research has shown how two key proteins bring about the oragnization of chromosomes and our genome.
Signaling Molecule Regulates Release of the Hunger Hormone Ghrelin
Researchers at UT Southwestern have identified that the blocking release of the hormone ghrelin may mediate low blood sugar effect in children taking beta blockers.
Telomere Replenishment in Real Time
Researchers have visualised the process of telomere attachment to chromosomes through single-molecule imaging.
Scroll Up
Scroll Down
Skyscraper Banner

SELECTBIO Market Reports
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
3,300+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,900+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!