BRIT1 allows DNA repair teams access to damaged sites

Jun 19, 2009

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.

Reporting online at this week, a research team led by scientists at The University of Texas M. D. Anderson Cancer Center shows that BRIT1 connects with another protein complex to relax DNA's tight packaging at the site of the damage.

"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 .

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 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.

Source: University of Texas M. D. Anderson Center (news : web)

Explore further: How do our muscles work? Scientists reveal important new insights into muscle protein

add to favorites email to friend print save as pdf

Related Stories

Chromatin remodeling complex connected to DNA damage control

Aug 09, 2007

When molecular disaster strikes, causing structural damage to DNA, players in two important pathways talk to each other to help contain the wreckage, scientists at The University of Texas M. D. Anderson Cancer Center report ...

Enhanced DNA-repair mechanism can cause breast cancer

Oct 15, 2007

Although defects in the "breast cancer gene," BRCA1, have been known for years to increase the risk for breast cancer, exactly how it can lead to tumor growth has remained a mystery. In the October 15, 2007, issue of the ...

Get in touch

Oct 30, 2007

When the genetic material inside a cell’s nucleus starts to fall apart, a protein called ATM takes charge and orchestrates the rescue mission. Surprisingly, for ATM to kick into full gear, the stretches of DNA flanking ...

Recommended for you

Genomes of malaria-carrying mosquitoes sequenced

1 hour ago

Nora Besansky, O'Hara Professor of Biological Sciences at the University of Notre Dame and a member of the University's Eck Institute for Global Health, has led an international team of scientists in sequencing ...

How calcium regulates mitochondrial carrier proteins

Nov 26, 2014

Mitochondrial carriers are a family of proteins that play the key role of transporting a chemically diverse range of molecules across the inner mitochondrial membrane. Mitochondrial aspartate/glutamate carriers are part of ...

Team conducts unprecedented analysis of microbial ecosystem

Nov 26, 2014

An international team of scientists from the Translational Genomics Research Institute (TGen) and The Luxembourg Centre for Systems Biomedicine (LCSB) have completed a first-of-its-kind microbial analysis of a biological ...

Students create microbe to weaken superbug

Nov 25, 2014

A team of undergraduate students from the University of Waterloo have designed a synthetic organism that may one day help doctors treat MRSA, an antibiotic-resistant superbug.

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.