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First protein crystal structure corrects wrong theory

Reb1 protein binds to DNA sequences, in one instance to control how DNA is transcribed into RNA; in the other, how DNA is replicated before cell division. This is the first time researchers were able to see the crystal form of Reb1 and find that it didn't perform as expected.

Before a cell can divide, DNA must be replicated exactly - if it is to be useful in a new daughter cell building tissue. During replication, two types of cell machinery are moving along the DNA strand — (1) transcription machinery and (2) replication machinery.

Transcription's first step is when an enzyme called RNA polymerase binds to the DNA double helix, unwinds and separates the two strands, and transcribes/copies that strand into messenger RNA (mRNA). The result is a completed strand of mRNA that can freely travel through the nuclear membrane and into the cytoplasm, to be made into proteins.

Replication is the process of copying the entire double helix of DNA so that there are two exact copies, just prior to cell division/mitosis. One DNA double helix copy for the original cell and one DNA double helix copy for the resulting daughter cell. Again, the DNA is unwound and its two strands separated., this time by an enzyme called DNA polymerase.

The similarities between both DNA replication and transcription processes involves binding complementary nucleic acids to DNA to create a new strand of either DNA or mRNA. An error in process can cause a change in a gene. Sometimes, if these two "machines" or processes collide and the DNA strand is broken, a mutation is caused which can be passed onto a new cell being formed.

Here is where Reb1 steps in.

"One way to prevent genome instability is to prevent replication from colliding with transcription. It's what terminator proteins do."

Deepak Bastia PhD, Endowed Chair for Biomedical Research, MUSC Department of Biochemistry and Molecular Biology, and co-senior author of the study.

At certain times transcription has to stop to conserve cell energy or to prevent uncontrolled growth. But during periods of instability — such as just before a cell divides — mistakes can happen.

The research, led by Deepak Bastia PhD, the Medical University of South Carolina (MUSC), Department of Biochemistry and Molecular Biology, and co-senior author of the study, is published in the Proceedings of the National Academy of Sciences. Researchers wanted to view the Reb1 structure as it binds to specific areas of DNA called terminator regions. Terminator regions were thought to act as physical barriers to transcription and replication "machinery" — sitting much like a wall to block both processes from colliding into each other.

In order to confirm that idea, Bastia's team cut off the Reb1 transcription terminator region (or tail). Though unable to stop transcription, it still was able to bind to DNA. So, the simple roadblock theory was wrong.

Carlos R. Escalante PhD, co-senior author from Virginia Commonwealth University, then made crystal formations of Reb1 on DNA, for scanning crystallography by the Brookhaven National Laboratory in New York state. The crystal structure then showed that, when bound to DNA, the transcription terminator tail of Reb1 can interact with a specific part of the transcriptional machinery, being a tether between the two.

Reb1 works as a traffic signal for coordinating transcription and gene replication, rather than as a roadblock as previously thought.

The connection between Reb1 and transcription is now more clear, but the team is still not sure exactly how terminator proteins stop transcription — a question driving their current work. Although a connection between terminator proteins and colorectal cancer is known to exist, more work on other cancers and aging still needs to be explored.

Bastia still suspects Reb1 coordination prevents the type of gene errors leading to many types of cell aging and tumor growth. Both processes result from uncontrolled transcription and replication.

The group is currently researching another type of terminator protein, work which Bastia hopes will lend knowledge to the diseases of aging.

Abstract Significance
Transcription termination of rRNA genes by RNA polymerase I (pol I) in fission yeast requires the binding of the Reb1 protein to a terminator site (Ter). Termination is physiologically necessary because its elimination can cause replication–transcription collision and induction of genome instability. Furthermore, without termination, pol I can become unproductively sequestered on the DNA templates. We have determined the crystal structure of fission yeast terminator protein Reb1-Ter complex revealing its functional architecture. Structure-guided functional analysis revealed that it is not just tight binding of the protein to Ter but protein–protein interactions with the Rpa12 subunit of RNA polymerase I that causes transcriptional arrest.

Reb1 of Schizosaccharomyces pombe represents a family of multifunctional proteins that bind to specific terminator sites (Ter) and cause polar termination of transcription catalyzed by RNA polymerase I (pol I) and arrest of replication forks approaching the Ter sites from the opposite direction. However, it remains to be investigated whether the same mechanism causes arrest of both DNA transactions. Here, we present the structure of Reb1 as a complex with a Ter site at a resolution of 2.7 Å. Structure-guided molecular genetic analyses revealed that it has distinct and well-defined DNA binding and transcription termination (TTD) domains. The region of the protein involved in replication termination is distinct from the TTD. Mechanistically, the data support the conclusion that transcription termination is not caused by just high affinity Reb1-Ter protein–DNA interactions. Rather, protein–protein interactions between the TTD with the Rpa12 subunit of RNA pol I seem to be an integral part of the mechanism. This conclusion is further supported by the observation that double mutations in TTD that abolished its interaction with Rpa12 also greatly reduced transcription termination thereby revealing a conduit for functional communications between RNA pol I and the terminator protein.

About The Medical University of South Carolina - MUSC
Founded in 1824 in Charleston, The Medical University of South Carolina is the oldest medical school in the South. Today, MUSC continues the tradition of excellence in education, research, and patient care. MUSC educates and trains more than 3,000 students and residents, and has nearly 13,000 employees, including approximately 1,500 faculty members. As the largest non-federal employer in Charleston, the university and its affiliates have collective annual budgets in excess of $2.2 billion. MUSC operates a 750-bed medical center, which includes a nationally recognized Children's Hospital, the Ashley River Tower (cardiovascular, digestive disease, and surgical oncology), Hollings Cancer Center (a National Cancer Institute designated center) Level I Trauma Center, and Institute of Psychiatry. For more information on academic information or clinical services, visit musc.edu. For more information on hospital patient services, visit muschealth.org.

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Apr 15, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Reb1 molecules
Image Credit: PNAS.org






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