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BRIT1 allows DNA repair teams access to damaged sites
June 22, 2009BRIT1 allows DNA repair teams access to damaged sites
Tumor-suppressor recruits help to overcome a barrier and fix cancer-causing defects
HOUSTON - Like a mechanic popping the hood of a car to get at a faulty engine, a tumor-suppressing protein allows cellular repair mechanisms to pounce on damaged DNA by overcoming a barrier to DNA access.
"Relaxing this barrier allows two different DNA repair pathways greater access to the damage, preventing flawed DNA from being passed on as the cell divides, which causes genomic instability leading to cancer," said senior author Shiaw-Yih Lin, Ph.D., assistant professor in M. D. Anderson's Department of Systems Biology.
BRIT1 is under-expressed in human ovarian, breast and prostate cancer cell lines. Lin and colleagues previously showed that the protein plays a key role in early detection of DNA damage.
Chromosomes are made of DNA that is tightly intertwined with proteins called histones to form chromatin. Chromatin is a very condensed structure that forms a natural barrier inhibiting access to genes, said first author Guang Peng, Ph.D., a post-doctoral fellow in Systems Biology. ATP-dependent chromatin remodeling is a fundamental mechanism used by cells to relax chromatin in DNA repair, but the detailed molecular mechanism by which it is recruited to DNA lesions in response to damage signaling has been largely unknown.
BRIT1 summons help
"Our studies demonstrate a novel mechanism by which BRIT1 recruits chromatin remodeling factors to DNA lesions to facilitate chromatin relaxation and DNA repair," Peng said.
A series of lab experiments showed that BRIT1 accomplishes this by enhanced binding to a known chromatin remodeling complex called SWI-SNF when a specific site on the complex is phosphorylated. BRIT1 also maintains the relaxation factor at the damage site.
The team showed that normal BRIT1 aids repair of double-stranded DNA breaks by allowing access to two repair pathways: homologous recombination (HR) and non-homologous end-joining (NHEC).
DNA repair efficiency dropped by between 40 and 60 percent in cells with BRIT1 knocked down that were then exposed to ionizing radiation, allowing many damaged cells to divide and pass on their genetic defects.
Potential for cancer treatment
Having shown that BRIT1 deficiency impairs HR repair, Peng said one solution the team is examining is to treat cancer cells lacking BRIT1 with PARP inhibitors, drugs that specifically kill HR-deficient cancer cells.
BRIT1 mutations are known to cause a neurological condition called primary microcephaly, in which the brain develops to only one third of normal size. The team showed that in experiments using cells derived from primary microcephaly patients that BRIT1 dysfunction may specifically contribute to development of the neurological disease by failing to bind to SWI-SNF to relax chromatin.
University of Texas M. D. Anderson Cancer Center
Chromatin Current Events and Chromatin News RSSGerton Lab determines the composition of centromeric chromatin
The Stowers Institute's Gerton Lab has provided new evidence to clarify the structure of nucleosomes containing Cse4, a centromere-specific histone protein required for proper kinetochore function, which plays a critical role in the process of mitosis. The work, conducted in yeast cells, was published in the most recent issue of Molecular Cell.
Researchers identify protein-telomere interactions that could be key in treating cancer
A team of researchers from The Wistar Institute have shown that a large non-coding RNA in mammals and yeast plays a central role in helping maintain telomeres, the tips of chromosomes that contain important genetic information and help regulate cell division.
Protein plays unexpected role protecting chromosome tips
A protein specialist that opens the genomic door for DNA repair and gene expression also turns out to be a multi-tasking workhorse that protects the tips of chromosomes and dabbles in a protein-destruction complex, a team lead by researchers at The University of Texas M. D. Anderson Cancer Center reports in the Aug. 13 edition of Molecular Cell.
Raising the alarm when DNA goes bad
Our genome is constantly under attack from things like UV light and toxins, which can damage or even break DNA strands and ultimately lead to cancer and other diseases.
Conaway Lab uncovers function of potential cancer-causing gene product
The Stowers Institute's Conaway Lab has uncovered a previously unknown function of a gene product called Amplified in Liver Cancer 1 (Alc1), which may play a role in the onset of cancer.
LincRNAs serve as genetic air-traffic controllers
Earlier this year, a scientific team from Beth Israel Deaconess Medical Center (BIDMC) and the Broad Institute identified a class of RNA genes known as large intervening non-coding RNAs or "lincRNAs," a discovery that has pushed the field forward in understanding the roles of these molecules in many biological processes, including stem cell pluripotency, cell cycle regulation, and the innate immune response.
Novel DNA vaccine leads to kidney damage prevention in systemic lupus erythematosus models
DNA vaccination using lupus autoantigens and interleukin-10 (IL-10, a cytokine that plays an important role in regulating the immune system) has potential as a novel therapy to induce antigen specific tolerance and may help to prevent kidney damage in patients with systemic lupus erythematosus (SLE).
USC researchers identify DNA mutation that occurs at beginning point of T-cell lymphoma
Researchers at the Keck School of Medicine of the University of Southern California (USC) have identified a key mechanism that causes chromosomes within blood cells to break-an occurrence that marks the first step in the development of human lymphoma.
Cocaine-linked genes enhance behavioral effects of addiction
New research sheds light on how cocaine regulates gene expression in a crucial reward region of the brain to elicit long-lasting changes in behavior.
Farnesoid X receptor regulates cystathionase
The expression and activity of Cystathionase is reduced in rodent models of liver injury, leading to hyper-homocysteinemia and impaired generation of hydrogen sulphide, two factors that contribute to endothelial dysfunction and increased intrahepatic resistance.
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