生物谷报道：研究人员报告说，一组复合蛋白质与肿瘤抑制基因(也被称为乳腺癌易患基因)BRCA1一起工作来修复DNA。虽然BRCA1的确切功能现在仍然不清楚，但是这些发现给对癌症发展和治疗感兴趣的研究人员提供了该基因的更多线索，BRCA1的突变与乳腺癌、卵巢癌、输卵管癌、前列腺癌、以及结肠癌有关。
Bin Wang和共同作者发表在最新一期《科学》杂志上的研究显示，BRCA1被合作伙伴蛋白质Abraxas 和Rap80 调动到DNA修复位置来修复DNA受损的细胞。Abraxas蛋白质调解Rap80和BRCA1的相互作用。Rap80被招到有DNA损伤的细胞的一个部位。根据Bijan Sobhian和同事、以及Hongtae Kim和共同作者的报告，Raps80将BRCA1标定到DNA损伤的位置，并且在正确的DNA损伤修复响应中起关键作用。在一项涉及DNA损伤修复系统的调节响应中有关蛋白质的大规模研究中，Shuhei Matsuoka和同事发现了900多个涉及700多个蛋白质的位置。这个新数据库揭示了比期待的更大的DNA损伤响应网络，同时显示带有DNA损伤的细胞完全改变了其生理。这个数据库是研究癌症和神经退化疾病的研究人员寻找新候选基因的资源。John H. J. Petrini针对四篇相关的论文撰写了一篇研究评述。
Fig. 1. Identification of Abraxas and RAP80 as proteins interacting with BRCA1-BRCT domains. (A) Binding of phosphorylated ABRA1 peptides to purified recombinant BRCA1-BRCT domains. Biotinylated peptides on streptavidin beads associated with purified recombinant GST-BRCA1-BRCT was visualized by Coomassie staining. The # symbol indicates a phosphate resides on the previous residue. (B) Specific binding of Abraxas to BRCA1-BRCT domains. Hemagglutinin-tagged ABRA1 (HA-ABRA1) was expressed in 293T cells, and cell lysates were incubated with various purified GST-tagged BRCT domains. (C) HA-ABRA1 association with endogenous BRCA1 is dependent on Ser406 phosphorylation. HA-ABRA1 wild-type or mutant proteins were expressed in 293T cells. (D) Phosphorylation of Ser406 of ABRA1 in vivo. Lysates prepared from 293T cells were untreated or treated with IR, untreated or treated with -phosphatase. (E) Immunoprecipitation of Abraxis with phospho-SQ or TQ antibodies. (F) RAP80 was identified in a TAP purification of BRCA1-BRCT domain–associated proteins. Retroviruses expressing either TAP only (TAP) or C-terminal TAP-tagged BRCT domain of BRCA1 (BRCT-TAP) were introduced into HeLa cells, and the infected cells were used for purification. A Coomassie-stained gel is shown. (G) Phosphorylation of RAP80 in response to IR. (H) Recognition of RAP80 by phospho-antibodies to ATM-ATR substrates. Proteins were immunoprecipitated from 293T cells lysates with antibodies to RAP80 and probed with the indicated antibodies. [View Larger Version of this Image (136K JPEG file)]
原文出处：
Science 25 May 2007 Vol 316, Issue 5828,
Abraxas and RAP80 Form a BRCA1 Protein Complex Required for the DNA Damage Response
Bin Wang, Shuhei Matsuoka, Bryan A. Ballif, Dong Zhang, Agata Smogorzewska, Steven P. Gygi, and Stephen J. Elledge
Science 25 May 2007: 1194-1198.
The breast cancer tumor suppressor BRCA1 is recruited to sites of DNA damage by partner proteins that help it to recognize ubiquitinated proteins.
Abstract »| Full Text »| PDF »| Supporting Online Material »|
相关基因：
BRCA1
Official Symbol: BRCA1 and Name: breast cancer 1, early onset [Homo sapiens]
Other Aliases: BRCAI, BRCC1, IRIS, PSCP, RNF53
Other Designations: BRCA1/BRCA2-containing complex, subunit 1; breast and ovarian cancer susceptibility protein 1
Location: 17q21
Chromosome: 17 Annotation: NC_000017.9 (38530993..38449839, complement)
MIM: 113705
GeneID: 672
UIMC1
Official Symbol: UIMC1 and Name: ubiquitin interaction motif containing 1 [Homo sapiens]
Other Aliases: RAP80, X2HRIP110
Other Designations: receptor associated protein 80; retinoid x receptor interacting protein
Location: 5q35.2
Chromosome: 5 Annotation: NC_000005.8 (176366048..176264611, complement)
MIM: 609433
GeneID: 51720
作者简介：
Stephen J. Elledge, Ph.D.
Many clues to how cancer develops have come from probing the cell cycle—the predictable, yet complex series of steps that culminate with cell division. Research by geneticist Stephen J. Elledge has uncovered important clues about what drives the cell cycle and how cells sense and respond to DNA damage.
He has also contributed on a broad level to advances in scientific disciplines by developing new cloning methods, as well as building cDNA libraries, collections of DNA snippets that code for proteins.
Growing up in Paris, Illinois, in the 1960s, one of Elledge's favorite toys was a chemistry set, and he spent countless hours carrying out all sorts of experiments. "God only knows what I thought I was doing, but I loved it," he recalled. Eventually, however, one of his concoctions blew up in his grandmother's kitchen, staining the ceiling. Elledge was sent to his room, and the chemistry set was banished to the basement. But this setback did not quell his desire to become a chemist.
The first in his family to go to college, Elledge attended the University of Illinois on a scholarship and majored in chemistry. But he was drawn to the field of biology after hearing about recombinant DNA during a senior year biochemistry course. "The potential for transforming biology was very clear, even stunning," Elledge remembers. "And I decided I wanted to be a part of that."
While pursuing a Ph.D. at the Massachusetts Institute of Technology, Elledge often found time for side projects, and he made a hobby out of developing new methods for generating recombinant DNA. Once, frustrated by his lack of success in using existing cloning methods, Elledge combined one of his earliest discoveries, the hybrid lambda-plasmid cloning vector, which was capable of making very large cDNA libraries, with his knowledge of yeast genetics, to invent a cloning technique that could genetically select protein-protein interactions from a very large library. "This technique and the 20 different cDNA libraries I made and freely distributed had a large impact on helping other labs identify important interacting partners for the proteins they were interested in," Elledge explained. "I firmly believe that new technology drives science and generally has a much
larger impact than individual basic science discoveries."
It was during a postdoctoral fellowship at Stanford University that Elledge began to focus his attention on the cell cycle. By accident, he cloned a family of genes known as ribonucleotide reductases, and later found that they were activated by DNA damage and regulated by the cell cycle. Soon after this discovery, Elledge attended a lecture by Paul Nurse, a scientist who later won the Nobel Prize in Physiology or Medicine for his cell cycle research. Nurse had recently isolated the human homolog of a key cell cycle gene, Cdc2, and his studies indicated that cell cycle regulation was functionally conserved from yeast to humans and that many human cell cycle genes could be isolated by looking for complimentary genes in yeast.
This message struck a chord with Elledge, and he set to work by first building a human cDNA library that could be expressed in yeast. Using this library, he identified a gene known as Cdk2, which is related to the gene previously isolated by Nurse. Cdk2, Elledge discovered, controls the transition from the G1 to the S phase of the cell cycle, and errors in this step that often lead to cancer.
Elledge, with his colleague Wade Harper, also isolated the p21 gene, which he demonstrated was the first of a family of Cdk2 inhibitors. The same gene was also found to be regulated by the cancer gene p53. Mutations in this gene occur in about half of all cancers. Elledge also discovered that the p57 gene, a member of the p21 family, is mutated in individuals with the Beckwith-Wiedemann syndrome, a disease that causes familial overgrowth and an increased risk of cancer.
While looking for additional cell cycle genes, Elledge and his colleagues identified the F-box, a conserved motif that is present in some proteins. F-box-containing proteins recognize specific protein sequences and mark them with ubiquitin for destruction by the cell's built-in shredder, a multiprotein structure called the proteasome. Increased levels of certain proteins can disrupt the cell cycle, so destroying them is one way to ensure that cells continue to divide normally or stop dividing all together, as required by the organism.
Elledge's research has also led to important discoveries about how cells detect and repair DNA damage, uncovering a whole signal transduction mechanism that alerts cells to chromosome defects. He recently identified the Chk2 enzyme, which activates the tumor-suppressor p53 to prevent cells with damaged DNA from dividing. When this enzyme is missing or defective, the "brakes" on cell division are released, increasing the risk of cancer. In other studies, he demonstrated that a protein known as ATM is a "trigger" for the protein BRCA1 to repair DNA damage. Mutations in ATM and BRCA1 together may account for nearly 10 percent of all breast cancers.
The point of the research, for Elledge, is not just merely an academic exercise in how things work, but an attempt to get to the roots of cancer and other health problems. "I have always wanted to make an impact on the world, to have my life on earth count for something," he said. "By contributing to basic research, I hope my work can accelerate discoveries to improve the lives and health of people."
Dr. Elledge is also Gregor Mendel Professor of Genetics in the Department of Genetics at Harvard Medical School and at Brigham and Women's Hospital.
RESEARCH ABSTRACT SUMMARY:
Stephen Elledge is interested in understanding cell cycle control and the cellular response to DNA damage. He is also interested in the development of genetic technologies to aid in gene and drug discovery.
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