ScienceDaily (Dec. 30, 2009) — In order to preserve our DNA, cells have developed an intricate system for monitoring and repairing DNA damage. Yet precisely how the initial damage signal is converted into a repair response remains unclear. Researchers at the Salk Institute for Biological Studies have now solved a crucial piece of the complex puzzle.
The protein CtIP is recruited to sites of DNA damage in human cells, where it helps convert the initial DNA damage signal into a repair response. (Credit: Courtesy of Dr. Zhongsheng You, Washington University School of Medicine.)
In a forthcoming article in the Dec. 24 issue of Molecular Cell, they show that a protein named CtIP plays an essential role in the DNA damage "signal-to-repair" conversion process. "Being able to repair damaged DNA is extremely important; the cell has to know when it has received this type of damage and respond appropriately," explains Tony Hunter, Ph.D., American Cancer Society Professor in the Molecular and Cell Biology Laboratory and director of the Salk Institute Cancer Center, who led the study. "Failure to do so can have disastrous consequences."
The DNA in our cells is under constant attack from reactive chemicals generated as byproducts of cellular metabolism. In addition, it is assaulted by x-rays, ultraviolet radiation from the sun, and environmental carcinogens such as tobacco smoke. As a result of this continuous bombardment, some studies have estimated that the DNA in a single human cell gets damaged over 10,000 times every day.
If not repaired properly, the damage leads to mutations, which over time can cause cancer. "As a result, individuals with an inherited impairment in DNA repair capability are often at increased risk of cancer," notes first author Zhongsheng You, Ph.D., a former postdoctoral researcher at the Salk Institute and now an assistant professor at Washington University School of Medicine in St. Louis.
DNA consists of two intertwined strands so that when the DNA is broken, two ends are revealed, one from each strand. In order to repair the DNA break, one strand is trimmed away -- or resected -- like a loose thread, leaving only the second strand. This exposed strand then searches for a copy of itself (located on its sister chromosome), and "photocopies" past the broken region, repairing the DNA and zipping itself back up.
In yeast, CtIP is required for resection of the broken end, and since it is also recruited to sites of DNA damage in human cells, Hunter's team wanted to know whether CtIP plays a similar role there. To find out, they depleted CtIP from human cells and caused DNA damage. Without the CtIP, they discovered, the cells could no longer trim back the damaged DNA strands, which brought the whole repair process to an abrupt halt.
"It looks like CtIP recruitment is a very important control point in the DNA repair process," You observes. "Once CtIP is recruited, resection and repair begin, so regulating CtIP recruitment is one way to regulate DNA repair itself."
...
Read more here/Leia mais aqui.
+++++
Molecular Cell
Volume 36, Issue 6, 24 December 2009, Pages 954-969
CtIP Links DNA Double-Strand Break Sensing to Resection
Zhongsheng You1, 2, , , Linda Z. Shi4, Quan Zhu3, Peng Wu1, You-Wei Zhang2, 6, Andrew Basilio4, Nina Tonnu3, Inder M. Verma3, Michael W. Berns4, 5 and Tony Hunter2, ,
1 Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA
2 Molecular and Cell Biology Laboratory, The Salk Institute, La Jolla, CA 92037, USA
3 Laboratory of Genetics, The Salk Institute, La Jolla, CA 92037, USA
4 Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA
5 Beckman Laser Institute and Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92715, USA
Received 15 March 2009; revised 18 September 2009; accepted 3 December 2009.
Published: December 24, 2009. Available online 24 December 2009.
Summary
In response to DNA double-strand breaks (DSBs), cells sense the DNA lesions and then activate the protein kinase ATM. Subsequent DSB resection produces RPA-coated ssDNA that is essential for activation of the DNA damage checkpoint and DNA repair by homologous recombination (HR). However, the biochemical mechanism underlying the transition from DSB sensing to resection remains unclear. Using Xenopus egg extracts and human cells, we show that the tumor suppressor protein CtIP plays a critical role in this transition. We find that CtIP translocates to DSBs, a process dependent on the DSB sensor complex Mre11-Rad50-NBS1, the kinase activity of ATM, and a direct DNA-binding motif in CtIP, and then promotes DSB resection. Thus, CtIP facilitates the transition from DSB sensing to processing: it does so by binding to the DNA at DSBs after DSB sensing and ATM activation and then promoting DNA resection, leading to checkpoint activation and HR.
Author Keywords: DNA; PROTEINS
+++++
Professores, pesquisadores e alunos de universidades públicas e privadas com acesso ao site CAPES/Periódicos podem ler gratuitamente este artigo da Molecular Cell e de mais 15 mil publicações científicas.
