Navigation Links
Enzyme helps cancer cells avoid genetic instability
Date:1/21/2013

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
news@rupress.org
212-327-8603
Rockefeller University Press
Source:Eurekalert  

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:
*Name:
*Comment:
*Email:
Related Image:
Enzyme helps cancer cells avoid genetic instability
(Date:1/20/2016)... Jan. 20, 2016  Synaptics Incorporated (NASDAQ: ... solutions, today announced sampling of S1423, its newest ... and small screen applications including smartwatches, fitness trackers, ... round and rectangular shapes, as well as thick ... with moisture on screen, while wearing gloves, and ...
(Date:1/15/2016)... SAN JUAN, Puerto Rico , Jan. 15, 2016 ... forcing companies big and small to find new ways ... data driven culture. iOS and ... their device based on biometrics, transforming it into a ... can request that users swipe their fingerprint on their ...
(Date:1/13/2016)... DUBLIN , January 13, 2016 ... has announced the addition of the  ... - Estimation & Forecast (2015-2020)" ... http://www.researchandmarkets.com/research/7h6hnn/india_biometrics ) has announced the ... & Identification Market - Estimation & ...
Breaking Biology News(10 mins):
(Date:2/8/2016)... , Feb. 8, 2016  CytRx Corporation (NASDAQ: ... company specializing in oncology, today announced that it ... agreement with Hercules Technology Growth Capital, Inc. and ... million in financing. --> ... $25 million of financing under the loan and ...
(Date:2/8/2016)... ... ... Information Management Services ( IMS ) is pleased to announce a major upgrade ... and is so significant it was endowed with a new name, BSI Engage. ... a streamlined layout and a more intuitive format for navigating the system. ...
(Date:2/8/2016)... , Feb. 8, 2016  Diplomat Pharmacy, Inc. (NYSE: DPLO) announced today that its new website ... pharmacy resource–user-centric, story-driven, knowledge-based and mobile-friendly. Visit the ... ... ... "The goal was to ...
(Date:2/5/2016)... N.C. , Feb. 5, 2016  In the ... role for a host of launch activities including the ... of this launch activity is especially high in the ... Best Practices and the Role of Medical ... help companies focused on oncology therapies find better ways ...
Breaking Biology Technology: