New Study Discovers Cancer-Relevant Protein Shield

Researchers Discover New DNA Repairers
A research team, led by Chuna Choudhary and Jiri Lukas, at the Novo Nordisk Foundation Center for Protein Research at the Faculty of Health and Medical Sciences at the University of Copenhagen, used advanced technology (mass spectrometry) to uncover previously unknown proteins that are involved in repairing damages to the DNA.

To do this, they genetically engineered human cells to “tag” key proteins that were already known to repair DNA and looked at other proteins that interact with them. This sophisticated analysis of “networks of DNA repair” allowed the researchers to get a detailed map of DNA repairing proteins and to discover new ones.

“This is very similar to using social media, such as Facebook, for finding out interactions of a person. By analyzing social network profile of a person we can find links to the individuals he/she interacts with, but who are unknown to us”, says Rajat Gupta, who is the first author of the study. Insufficient therapies
DNA is the blueprint of life, and cells closely guard their DNA to protect against any damage. Failure of these mechanisms can be catastrophic.

Faulty DNA repair is the fundamental cause of most cancers and mutant cells from the gene BRCA1 play an important role in the development of hereditary breast cancer. Basically, the BRCA proteins are involved in fixing broken DNA in a cell, and because BRCA mutant cells cannot accurately repair their DNA, it leads to the development of cancer.

The risk of developing aggressive forms of cancer in BRCA positive women is so high that some women even choose to have both breasts removed (mastectomy) as a preventative treatment. The most well-known case was when the actress Angelina Jolie chose to have both her breasts removed due to a BRCA-positive diagnosis. 

Breakthrough advances in the past years have led to highly promising drugs, called PARP inhibitors, that effectively cures BRCA positive cancers. Unfortunately, not all patients respond to the drug and many of those who do respond initially develop resistance to these drugs after a period of treatment. Researchers are therefore actively trying to understand the mechanisms that cause the resistance and to find new targets that can be used to treat these resistant cancers.

New Protein Shield affects Cancer Therapy
The Novo Nordisk Foundation Center for Protein Research is a leader in protein research and uses large amounts of health data, DNA sequencing and mass spectrometric analysis to find new proteins that can be the target of new drugs against a wide range of diseases.

The researchers behind the new Cell study have uncovered a whole new network of proteins that play a crucial role in the repair of DNA strands in BRCA positive women. The network protects against further damage to DNA damage and allows other proteins to repair the DNA strings. The researchers have therefore given the network the name "Shieldin" - the protein shield.

The new research result also provide interesting new insights into how BRCA1-faulty tumors can develop resistance to PARP inhibitors. Understanding these mechanisms will aid in deciding which patients may benefit from the treatment and designing potential new therapies for patients who develop resistance to these drugs.

“We have gained new, unique insight into protein networks of the DNA repair process and identified a new “protein shield” that protects broken DNA ends and thereby helps in repairing damaged DNA. Shieldin also affects treatment responses to PARP inhibitor drugs, that are among the most advanced and effective therapy for BRCA positive cancers. The new findings may contribute in making decisions for treating cancer patients and to understand the mechanisms of resistance to PARP inhibitor drugs,” says Professor Chuna Choudhary.

The next step will be to further understand details of protein networks, how exactly Shieldin protects DNA, and how it impacts cancer resistance to PARP inhibitor. Researchers will also be interested to understand whether Shieldin could be used as a new cancer drug target.

Fact box: Breast cancer is one the most frequently occurring cancer in women worldwide, and hundreds of thousands of new cases are diagnosed with the disease every year. Around 5-10 percent of breast cancer is hereditary, meaning that a woman inherits faulty breast cancer-causing genes from her parents. For example, mutations in BRCA1 gene are found in many cases of hereditary breast cancer. The Danish Healthcare service conduct national screenings and offer genetic tests to discover the risk early and provide preventive treatment.

Read the entire study “DNA repair network analysis reveals Shieldin as a key regulator of NHEJ and PARP inhibitor sensitivity” in Cell here.

The study was carried out at the Novo Nordisk Foundation Center for Protein Research (CPR) at the University of Copenhagen in close collaboration with the teams of Dr. Jiri Lukas and Niels Mailand at CPR, Dr. Andre Nussenzweig from NIH, and Dr. Michael Lammers from University of Cologne. 

Contact

Prof. Chuna Choudhary, email: chuna.choudhary@cpr.ku.dk , phone: 0045 24426643