Navigation Links
Enzyme helps cancer cells avoid genetic instability

Cancer cells are resourceful survivors with plenty of tricks for staying alive. Researchers have uncovered one of these stratagems, showing how cells lacking the tumor suppressor BRCA1 can resume one form of DNA repair, sparing themselves from stagnation or death. The study appears in the January 21st issue of The Journal of Cell Biology.

The BRCA1 protein helps to mend double-strand DNA breaks by promoting homologous recombination. Without it, cells can amass broken, jumbled, and fused chromosomes, which may cause them to stop growing or die. Although cells lacking BRCA1 seem like they should be vulnerable, loss of the protein instead seems to boost abnormal growth.

Recent studies have shown that cells lacking BRCA1 compensate by cutting back on 53BP1. This protein helps orchestrate a different DNA repair mechanism, nonhomologous end joining (NHEJ), and it thwarts a key step in homologous recombination. Researchers think that, in cells without BRCA1, 53BP1 spurs excessive NHEJ that can cause fatal chromosomal chaos. But with 53BP1 out of the way, the cells are able to resume homologous recombination. That might explain why cells that lack BRCA1 and eliminate 53BP1 can withstand traditional chemotherapy compounds and PARP inhibitors, a new generation of anti-cancer drugs that are in clinical trials. But how do cancer cells turn down 53BP1?

Researchers previously found that certain mutant fibroblasts increase production of cathepsin L, a protease that destroys 53BP1. BRCA1-deficient cancer cells take advantage of the same mechanism, according to a team of researchers led by Susana Gonzalo from the Washington University School of Medicine. When they cultured breast cancer cells that were missing BRCA1, the cells stopped growing. After two weeks of lethargy, however, some cells, which the researchers dubbed BOGA cells (BRCA1-deficient cells that overcome growth arrest), began to divide again. These cells showed increased levels of cathepsin L and reduced amounts of 53BP1. Eliminating cathepsin L from BOGA cells or dosing them with vitamin D, a cathepsin L inhibitor, prevented the decline in 53BP1 abundance.

To find out whether boosting cathepsin L levels enabled the cancer cells to restart homologous recombination, the researchers monitored sites of DNA damage tagged by RAD51, a protein that helps promote homologous recombination. The cells that had stopped growing did not display RAD51 foci, but these foci were prevalent in BOGA cells with reduced 53BP1. Removing cathepsin L from BOGA cells increased 53BP1 levels and diminished the number of RAD51 foci.

If cells can't perform homologous recombination, they turn to repair mechanisms such as NHEJ that can lead to jumbled chromosomes. However, after DNA-breaking doses of radiation, BOGA cells exhibited few chromosome defects. The number of these flaws climbed after the researchers stabilized 53BP1 levels by inhibiting cathepsin L or trimming its abundance.

The team then analyzed tumor samples from breast cancer patients. Researchers suspect that cathepsin L attacks 53BP1 by entering the nucleus. Samples from patients with BRCA1 mutations or with triple-negative breast canceran aggressive form of the diseaseshowed high levels of nuclear cathepsin L and reduced quantities of 53BP1. That suggests tumors in these patients hike the amounts of cathepsin L in the nucleus to break down 53BP1 and restore homologous recombination.

"It's a new pathway that explains how breast cancer cells lose 53BP1," says Gonzalo. How cancer cells boost nuclear cathepsin L levels is unclear, she notes.

Triple-negative breast cancers are currently identified by their lack of Her2 and the estrogen and progesterone receptors. The work suggests that another trio of measurementsthe amounts of 53BP1, cathepsin L, and vitamin D receptor in the nucleusmight help identify patients that are resistant to current breast cancer treatments. These people might respond to cathepsin inhibitors, some of which are undergoing animal testing. These compounds might steer the cells away from homologous recombination and leave them vulnerable to other therapies.


Contact: Rita Sullivan King
Rockefeller University Press

Related biology news :

1. Penn biologists identify a key enzyme involved in protecting nerves from degeneration
2. New immune defense enzyme discovered
3. Genzyme/ACMG Foundation Genetics Training Award in Clinical Biochemical Genetics announced
4. ORNL process improves catalytic rate of enzymes by 3,000 percent
5. Scientists discover enzyme that could slow part of the aging process in astronauts -- and the elderly
6. New screening technique yields elusive compounds to block immune-regulating enzyme
7. UCLA scientists discover how key enzyme involved in aging, cancer assembles
8. Is it a rock, or is it Jell-O? Defining the architecture of rhomboid enzymes
9. Brain enzyme is double whammy for Alzheimers disease
10. Ancient enzymes function like nanopistons to unwind RNA
11. Remarkable enzyme points the way to reducing nitric acid use in industry
Post Your Comments:
Related Image:
Enzyme helps cancer cells avoid genetic instability
(Date:11/9/2015)... Calif. , Nov. 9, 2015  Synaptics Inc. ... interface solutions, today announced broader entry into the automotive ... solutions that match the pace of consumer electronics human ... biometric sensors are ideal for the automotive industry and ... Europe , ...
(Date:10/29/2015)... , Oct. 29, 2015  The J. Craig Venter ... titled, "DNA Synthesis and Biosecurity: Lessons Learned and Options ... of Health and Human Services guidance for synthetic biology ... --> --> ... has the potential to pose unique biosecurity threats. It ...
(Date:10/29/2015)... 2015 NXTD ) ("NXT-ID" ... on the growing mobile commerce market and creator ... a leading marketplace to discover and buy innovative ... wallet on StackSocial for this holiday season.   ... "Company"), a biometric authentication company focused on the ...
Breaking Biology News(10 mins):
(Date:11/25/2015)... , Nov. 25, 2015 /PRNewswire/ - Aeterna Zentaris ... that its business and prospects remain fundamentally strong ... Zoptrex™ (zoptarelin doxorubicin) recently received DSMB recommendation to ... completion following review of the final interim efficacy ... 2 Primary Endpoint in men with heavily pretreated ...
(Date:11/25/2015)... , November 25, 2015 ... Research Report is a professional and in-depth study ...      (Logo: ) , ... of the industry including definitions, classifications, applications and ... provided for the international markets including development trends, ...
(Date:11/24/2015)... FAR HILLS, N.J. (PRWEB) , ... November 24, 2015 , ... ... University, as the recipient of the 2016 USGA Green Section Award. Presented annually since ... of golf through his or her work with turfgrass. , Clarke, of ...
(Date:11/24/2015)... Nov. 24, 2015 /CNW/ - iCo Therapeutics ("iCo" or ... financial results for the quarter ended September 30, ... Canadian dollars and presented under International Financial Reporting ... ," said Andrew Rae , President ... iCo-008 are not only value enriching for this ...
Breaking Biology Technology: