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| Repairing Broken DNA And The Consequences If We Can't |
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| SciMed - Genetics & Genome | |||
| TS-Si News Service | |||
| Sunday, 27 July 2008 18:00 | |||
 
In general, we all have 23 pairs of chromosomes (total of 46). One chromosome in each pair comes from each parent. If it is our turn to make sperm or eggs, we ordinarily drop one chromosome from each pair so the sperm or egg contributes only 23 chromosomes to the future pregnancy.
The outcome of the pregnancy depends on the positioning of each chromosome to the egg or sperm. As shown above, if you have one normal chromosome 4 and a normal 20, you also have one copy of each that contains the translocated information from the other chromosome. • If the egg gets the normal chromosomes 4 and 20, the offspring will be normal. • If the egg gets both translocated chromosomes, the baby will be normal, but carry the parent's chromosomal pattern. In other cases, the developing embryo gets too much of one chromosome and not enough of the other. • If the egg gets a good chromosome 4 and a translocated 20, there will be an extra portion of 4 and a missing portion of 20 (called unbalanced translocation). • The same problem occurs if an egg gets a normal 20 and a translocated 4. Statistics suggest a rather uniform breakdown. • 50 percent of the eggs would likely generate unbalanced translocations, • 25 percent would be balanced translocations and • 25 percent would be normal. The balanced translocation carrier appears — and for almost all purposes is — normal, since there is no missing or extra chromosomal material. Miscarriage is the usual result for fetuses with an extra or missing chromosome. The exceptions include some cases of Down or Turner syndrome that result in live birth. In contrast, translocation problems occur when trying to conceive. Many pregnancies that result from chromosomal imbalances miscarry before the woman is even aware that she has conceived. Two-thirds of known pregnancies result in healthy live births. • one-third will be normal, • one-third will carry the balanced translocation, and • one-third will likely miscarry from an unbalanced chromosomal translocation. This condition is not related to a woman's age. It is relatively rare, making up less than 5 percent of all cases of recurrent pregnancy loss. Prenatal chromosomal screening is usually suggested for all continuing pregnancies.  DNA is broken? The genome itself is the source of our body and any unrepaired — or poorly repaired — breaks can have profound consequences. The result can be anomalous birth conditions and often-fatal diseases. Generally speaking, broken pieces of DNA in our cells reunite as they are repaired. These pieces tether together following a quick and precise [N1] process of mutual identification. A suppressor gene called ATM choreographs this fast-paced, but reliable, reassembly operation. But happens when an important mechanism for repair is itself broken?
Saccharomyces cerevisiae ATM orthologue suppresses break-induced chromosome translocations. Kihoon Lee, Yu Zhang & Sang Eun Lee. Nature 454(7203) 543-546. doi: 10.1038 / nature07054.
Sometimes the process goes awry. A known ATM
mutation predisposes children to cancers, while other conditions may be a result. In the July 23 issue of Nature, researchers at The University of Texas (UT) Health Science Center at San Antonio describe the ATM gene’s regulatory work more fully than ever before. Chromosomes are the tightly wrapped coils of DNA found in every cell. The paper fromm the Center’s Institute of Biotechnology is among the first to describe the molecular basis of errors occur when genes from one chromosome glom onto another chromosome. Ths is the process known as chromosome translocation.
The ATM gene
The ataxia telangiectasia mutated (ATM) gene provides instructions for making a protein that located primarily in the nucleus of cells. ATM helps control the rate at which cells grow and divide. This protein also plays an important role in the normal development and activity of several or body systems, including the both
nervous system and the immune system. Moreover, ATM is a tumor-suppressor gene. The ATM protein has also been recognized for its important role in recognizing recognizing damaged or broken DNA strands. DNA can be damaged by agents such as toxic chemicals or radiation. Breaks in DNA strands also occur naturally when chromosomes exchange genetic material during cell division.
The ATM protein coordinates DNA repair by activating enzymes that fix the broken strands. Efficient repair of damaged DNA strands helps maintain the stability of the cell's genetic information.
Because of its central role in cell division and DNA repair, the ATM protein is of great interest in research, with a particular focus by cancer researchers.
The occasional glitch
In
genetics, chromosomes that are not members of the same pair are called nonhomologous. An abnormality called chromosome translocation is caused by the rearrangement of parts between nonhomologous chromosomes. Translocations can be
Lead author Sang Eun Lee, Ph.D., associate professor of molecular medicine at the Health Science Center, suspected that chromosome translocations occur during DNA repair. DNA repair is the continuous process in which our genetic blueprint, or DNA, fixes damage caused by sunlight, diet, oxygen and chemicals that ding our DNA.
 Dr. Sang Eun Lee, Ph.D., is an associate professor of molecular medicine at The University of Texas (UT) Health Science Center at San Antonio and a member of the Cancer Development and Progression Program of the Cancer Therapy & Research Center. [N2]
“This DNA repair process is usually highly accurate and reliable, but occasionally DNA makes the mistake of reshuffling or jumbling together material.” … “Translocations are found in many cancers, particularly leukemia."
According to Lee, "The presence of translocations predicts the success or failure of treatments for these cancers.” A rare and aggressive cancer, Philadelphia chromosome-positive chronic myelogenous leukemia, involves translocation of genetic material from chromosomes 9 and 22, for example. “The thing we haven’t understood is how chromosome translocations happen,” Dr. Lee said. “Our study recreated translocations in yeast cells. We monitored the translocation events in the context of DNA repair, which we believed to be the culprit.”
ATM traffic control
The researchers observed ATM-led machinery that prohibits chromosome translocations during DNA repair. ATM “traffic-controls” many other proteins, Dr. Lee said.
“When damage occurs, a chromosome, like thread, can be broken,” he said. “With exposure to radiation or other mutating agent, a chromosome may break in multiple places. Thankfully our DNA moves to repair this.”
Snippets of DNA, separated from adjacent snippets of the same chromosome, must reunite with them quickly. “Partner selections are very important, and we found that this selection occurs in a very short window of time,” Dr. Lee said. “We also observed the tethering together. Again, the gene central to all of this is ATM.”
Role in cancer
The majority of children with ATM deficiency die at a young age from cancer. ATM mutation causes the disease ataxia telangiectsia. “We were missing why ATM causes cancers,” Dr. Lee said. “Its strategic role in DNA repair, described in this paper, explains it.”
These observations may make it possible to tweak cellular machinery to prevent translocations and to develop anti-cancer drugs that bypass ATM deficiency by regulating gene proteins that interact with ATM.
Yeast to humans
Dr. Lee said information gleaned from the yeast cell experiments is extremely relevant to human cells “since the DNA repair mechanism is extremely well conserved across species.”
“Dr. Lee is following these chromosome events in real time during the repair process,” said Z. Dave Sharp, Ph.D., associate professor and interim chairman of the Department of Molecular Medicine at the Health Science Center. “The proteins he studied are in yeast, but these proteins carry out the same function in human cells. That’s the reason this paper is in Nature.”
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