Abnormal DNA maintenance related to cancer
DNA, like houses and cars, needs ongoing maintenance. Rays of ultraviolet sunlight, chemical pollutants and normal biochemical processes in the cell can damage it. Cells routinely repair this damage before making proteins or copying DNA for cell division. The repairs are remarkably accurate in normal cells but cancer cells make far more mistakes in fixing their DNA. Alan Tomkinson, PhD, University of New Mexico Professor of Internal Medicine and Associate Director of Basic Research at the UNM Cancer Center, wants to understand why and how these repair mechanisms go awry in cancer cells. This understanding could lead to new targets for cancer drugs. Dr. Tomkinson recently won a 4-year $1 million grant renewal to continue his 18-year research investigation on DNA ligases, the enzymes that repair DNA strands.
DNA ligases fuse the backbone of a DNA strand. The strand is a long string of nucleotides that structurally resembles one half of a ladder sliced lengthwise through the rungs. Each nucleotide consists of a deoxyribose molecule with a phosphate molecule on one side and a base molecule on another. The phosphate of one nucleotide attaches to the deoxyribose of the adjacent nucleotide, forming the alternating phosphate-deoxyribose DNA strand backbone—the side of the ladder. In a DNA molecule—a full ladder—each base attaches to a complementary base on the mirror strand to form the rung-like structures that encode genes.
Products of normal cellular chemical reactions and DNA repair proteins that replace damaged bases can break the phosphate-deoxyribose backbone. If only one strand is broken, the overall DNA structure remains intact because the bases of the broken strand still attach to those of the second, unbroken strand. It is relatively simple for DNA ligases to fuse such single-strand breaks. The DNA molecule falls apart, however, if both strands are broken at the same time and in the same place. In this situation, the cell has several different options to repair these breaks, all of which end with a DNA ligase rejoining the DNA backbone. Dr. Tomkinson studies how DNA ligases work with other DNA repair proteins to repair damage to DNA.
These repair mechanisms are not perfect, though. "You can measure the frequency at which the cell will make a mistake," says Dr. Tomkinson. This error rate is very low in normal cells but the DNA of cancer cells has many changes. "The error rate is so low in normal cells that you would not expect to see cancer normally," says Dr. Tomkinson. "In the process of a normal cell turning into a cancer cell," he explains, "a certain number of changes must accumulate. So at some stage it appears that the mechanisms that normally repair DNA become abnormal."
In fact, these processes become so abnormal that DNA in cancer cells is vastly different from DNA in normal cells. Normal cells have 46 chromosomes; cancer cells frequently do not, a condition called aneuploidy. Normal cells have 23 pairs of chromosomes and the chromosomes of 22 of those pairs resemble each other. Cancer cells, in contrast, have many chromosomes that look vastly different and researchers can see these differences through modern staining techniques that allow them to stain each chromosome a different color. In normal cells, the chromosome pairs retain their color and stay monochromatic; cancer cells become multicolored because the cell links part of one chromosome to part of another. Called translocation, this shuffling of DNA pieces is common in some cancers. "A lot of leukemias have single translocations and they're stable events that you can see easily by cytogenetics," says Dr. Tomkinson. "In some breast cancers you see almost a complete shuffling of the genetic information. The chromosomes look more like a rainbow than like a single color and the sizes are mismatched."
So, Dr. Tomkinson is studying the enzymes that complete the repair of DNA, the DNA ligases, to learn how the process becomes abnormal. Humans have three types of DNA ligases named ligase I, ligase III, and ligase IV. Dr. Tomkinson is able to measure each ligase's activities in a cell. He has found that the type of ligase that is most active differs between a normal cell and a cancer cell. Normal cells have more ligase IV activity while cancer cells have more ligase III activity. Dr. Tomkinson's grant renewal will further investigate what each of these ligases do and how their activity differs between normal and cancerous cells. "If you know that cancer cells have an abnormality in how they handle DNA damage," he says, "you can selectively target that abnormality so that you kill the cancer cell without harming normal cells."
Provided by University of New Mexico Cancer Center
- Study: Cells prevent DNA repair Nov 23, 2005 | not rated yet | 0
- Single-DNA images give clues to breast cancer Oct 29, 2012 | not rated yet | 0
- Researchers find way to make cancer cells more mortal Jul 16, 2010 | not rated yet | 0
- New study sheds light on cancer-protective properties of milk Oct 03, 2012 | not rated yet | 0
- DNA Repair Teams’ Motto: 'To Protect and Serve' Nov 16, 2006 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Why is zone 1 in liver more prone to ischemic injury?
May 23, 2013 Hi, Is it because around central vein, there is only deoxygenated blood from the vein where as in the periphery there is hepatic artery. Also why...
How can there be villous adenoma in colon, if there are no villi there
May 22, 2013 As title suggest. Thanks :smile:
How can there be a term called "intestinal metaplasia" of stomach
May 21, 2013 Hello everyone, Ok Stomach's normal epithelium is simple columnar, now in intestinal type of adenocarcinoma of stomach it undergoes "intestinal...
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
- More from Physics Forums - Medical Sciences
More news stories
In recent years, microRNAs (miRNAs) and other non-coding RNAs are small molecules that help control the expression of specific proteins. In recent years they have emerged as disease biomarkers. miRNA profiles have been used ...
Cancer May 24, 2013 | not rated yet | 0
Cancer cells spread and grow by avoiding detection and destruction by the immune system. Stimulation of the immune system can help to eliminate cancer cells; however, there are many factors that cause the immune system to ...
Cancer May 24, 2013 | 5 / 5 (1) | 0
Researchers from London's Kingston University have begun a two-year study which could help prolong the lives of people with colorectal tumours.
Cancer May 24, 2013 | 5 / 5 (1) | 0
Transformative research from Western University has identified new hormones in the body which may suppress breast cancer and stimulate the regression of breast tumors.
Cancer May 24, 2013 | 5 / 5 (2) | 0
(Medical Xpress)—Curtin University researchers have found evidence that targeting specific cells in the body can reverse the effects of cancer on the immune system.
Cancer May 24, 2013 | 5 / 5 (4) | 0
(HealthDay)—Animals make great companions for senior citizens, but elderly people who always drive with a pet in the car are far more likely to crash than those who never drive with a pet, researchers have ...
1 hour ago | not rated yet | 0
Coenzyme Q10 decreases all cause mortality by half, according to the results of a multicentre randomised double blind trial presented today at Heart Failure 2013 congress. It is the first drug to improve heart failure mortality ...
9 hours ago | 5 / 5 (2) | 5
Heart failure accelerates the aging process and brings on early andropausal syndrome (AS), according to research presented today at the Heart Failure Congress 2013. AS, also referred to as male 'menopause', was four times ...
9 hours ago | not rated yet | 1
Mortality and length of stay are highest in heart failure patients admitted in January, on Friday, and overnight, according to research presented today at the Heart Failure Congress 2013. The analysis of nearly 1 million ...
9 hours ago | not rated yet | 0
(AP)—Department of Justice lawyers have again asked a federal appeals court in New York to delay lifting age restrictions and prescription requirements on an emergency contraceptive popularly known as the morning-after ...
9 hours ago | not rated yet | 0