It's the same for a cell--just before it divides, it recruits protein complexes that repair breakage that may have occurred along the linear DNA chains making up your 46 chromosomes. Without repair, damage caused by smoking, chemical mutagens, or radiation might be passed on to the next generation.
However, in 2005, investigators at the Salk Institute for Biological Studies observed that before cell division some of these cellular paramedics inexplicably idle at undamaged chromosome ends, known as telomeres. Apparently the telomeres' disheveled appearance --resembling that of broken DNA strands--raises a red flag.
Now, in a study published in the Nov. 17 issue of Cell, that same team led by Jan Karlseder, Ph.D, Hearst Endowment Assistant Professor in the Molecular and Cell Biology Laboratory, reveals why those repair crews are parked at the ends of chromosomes and in doing so answer fundamental questions about how chromosomal stability is maintained.
After the 2005 study, says Karlseder, "We formed a hypothesis that after telomeres replicate they need to be detected by the internal DNA damage machinery--otherwise they cannot form a protective structure, or chromosomal cap."
And that's exactly what the new study shows. Examining activity of telomeric and DNA repair proteins in cultured human cells, the investigators found that right before cell division cellular repair proteins (including one actually called the 9-1-1 complex) are recruited to exposed DNA ends. But rather than fixing what resembles a break, the repair crew, which first arrived at the scene, calls in a second conglomeration of repair proteins. This one, called the homologous recombination (HR) machinery, creates the protective structure.
"The HR machinery fixes any break in the genome that occurs during replication of DNA," explains post-doctoral researcher Ramiro Verdun, Ph.D., lead author of the 2005 and the current study. However, at telomeres, just before they unload their cellular repair truck, HR crews apparently realize where they are--at the end and not the middle of the DNA strand-- and reconfigure. "At telomeres, they invade and then stop," says Verdun. "They adopt a different strategy."
That strategy is to tuck in the ragged chromosomal tips and form the cap, thereby hiding those tips from enzymes whose job it is to reattach errant DNA strands. "Again it was surprising," says Karlseder of the versatile HR team. "The cell is very clever. It takes advantage of a machinery that's already there and whose job it is to repair damage, but at telomeres this machinery fulfills a very special 'repair' function."
Be thankful your cells are so clever. Erroneous fusion of chromosome ends would be disastrous, leading to cell death or worse. "When DNA at telomeres is repaired chromosomes fuse together. If these cells then divide you could get chromosome breakage and genome instability, which leads to cancer," explains Karlseder.
In fact, the reason that telomeres, which are synthesized by an enzyme known as telomerase, exist is to assure that chromosome ends remain intact through a lifetime of cell divisions. When asked if there are cancers in which telomerase activity goes awry, Karlseder answers with no hesitation: "Almost all of them."
In fact, many proteins contained in DNA repair complexes are defective in cancer. "Proteins that play an important role in the model we propose are mutated in several diseases," says Verdun. "In cells with those mutations, the telomeres are not normal--they are fused, broken, shorter, or longer--but they are not normal."
For Verdun one goal of basic science is to understand how normal cells behave with the goal of fixing them if something goes wrong. "We are working on normal human cells--not cancer cells," he explains. "But we cannot understand how badly behaved cancer cells work if we don't know how a normal cell functions."
Gina Kirchweger | EurekAlert!
Two Group A Streptococcus genes linked to 'flesh-eating' bacterial infections
25.09.2017 | University of Maryland
Rainbow colors reveal cell history: Uncovering β-cell heterogeneity
22.09.2017 | DFG-Forschungszentrum für Regenerative Therapien TU Dresden
Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.
A warming planet
Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.
The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...
Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...
Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!
When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...
For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.
Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...
19.09.2017 | Event News
12.09.2017 | Event News
06.09.2017 | Event News
25.09.2017 | Physics and Astronomy
25.09.2017 | Life Sciences
25.09.2017 | Physics and Astronomy