Novel Mechanism For DNA Replication Discovered

Novel Mechanism For DNA Replication Discovered: "Since the discovery of the structure of DNA by James Watson and Francis Crick in 1953, the paradigm for DNA replication has stated that the DNA itself codes for the appropriate pairings for replication. In other words, if a guanine base is on the original strand of DNA then its partner, a cytosine base, will pair to it on the replicated strand. In a study published in this week's issue of Science, researchers from Mount Sinai School of Medicine report on the first instance in which a protein, rather than the DNA, provides the coding information.

The study offers a specific mechanism by which cells cope with some of the most destructive carcinogens in the environment, including those in cigarette smoke. Many of these carcinogens preferentially damage DNA at guanine -- one of the four bases in DNA -- blocking, in some cases, the ability of the guanine to partner with cytosine, which can lead to mistakes during replication.

Aneel Aggarwal, PhD, and Deepak Nair, PhD, of the Department of Physiology and Biophysics at Mount Sinai School of Medicine and their colleagues at University of Texas Medical Branch, Galveston discovered that a protein called Rev1 DNA polymerase itself codes for a cytosine to be placed on the replicating strand. The cytosine is inserted based upon the coding information in Rev1 regardless of whether a guanine or another base is present on the DNA.

"This is the first time we have seen a protein serving as a template for DNA synthesis," said Dr. Aggarwal. "This provides an entirely new mechanism by which cells can replicate through DNA damaged by certain carcinogens. It thus opens a novel area of study with the potential for innovative approaches to prevention and treatment of cancer.""

The Mount Sinai Hospital / Mount Sinai School of Medicine

Synaptic Plasticity: BIOCHEMICAL MECHANISMS FOR TRANSLATIONAL REGULATION IN SYNAPTIC PLASTICITY

Nature Reviews Neuroscience - Reviews: "Changes in gene expression are required for long-lasting synaptic plasticity and long-term memory in both invertebrates and vertebrates. Regulation of local protein synthesis allows synapses to control synaptic strength independently of messenger RNA synthesis in the cell body. Recent reports indicate that several biochemical signalling cascades couple neurotransmitter and neurotrophin receptors to translational regulatory factors in protein synthesis-dependent forms of synaptic plasticity and memory. In this review, we highlight these translational regulatory mechanisms and the signalling pathways that govern the expression of synaptic plasticity in response to specific types of neuronal stimulation.

Translation factors and translational control mechanisms are downstream targets of several signalling pathways and are crucial in synaptic plasticity. Some forms of translational control alter general protein synthesis, whereas others regulate translation of specific messenger RNAs (mRNAs).
Translation initiation refers to the assembly of a translation-competent ribosome at the AUG start codon on an mRNA. The first step involves the binding of the translation-initiation factor eIF2, which is a G protein, to methionyl-transfer RNA in a GTP-dependent manner.eIF2 has three subunits (, and ), and the conversion of inactive eIF2GDP to active eIF2GTP by eIF2B is blocked by phosphorylation of eIF2. Four kinases that are present in the brain — PKR, HRI, PERK and GCN2 — phosphorylate eIF2 on Ser51.
The eIF2B enzyme complex consists of five polypeptides (–), with eIF2B catalysing guanine nucleotide exchange on eIF2. The importance of eIF2B function in the brain is highlighted by the fact that mutations in each eIF2B subunit can cause leukoencephalopathy with vanishing white matter.
The integrity of the eIF4F cap-binding complex and, therefore, translation efficiency, is regulated by 4E-BPs. Phosphorylation of 4E-BPs by the extracellular signal-regulated kinase (ERK), phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) signalling pathways is crucial for protein synthesis-dependent synaptic plasticity and memory.
The cap-binding protein eIF4E is phosphorylated by the protein kinases Mnk1 and Mnk2, which are phosphorylated and activated by ERK and p38. eIF4E phosphorylation is associated with synaptic plasticity and memory.
In addition to regulating 4E-BP phosphorylation and function, mTOR directly phosphorylates and activates the S6 kinase (S6K), which phosphorylates the ribosomal protein S6, an essential component of the small, 40S ribosomal subunit. S6K and S6 phosphorylation have been implicated in synaptic plasticity and memory.
The cytoplasmic polyadenylation element (CPE) in the 3'-untranslated region is important in extension of the poly(A) tail and translation activation. Recent evidence indicates a crucial role for CPE-binding protein in long-term facilitation in Aplysia californica and in hippocampal synaptic plasticity."

Eric Klann & Thomas E. Dever
BIOCHEMICAL MECHANISMS FOR TRANSLATIONAL REGULATION IN SYNAPTIC PLASTICITY
Nature Reviews Neuroscience 5, 931-942 (2004); doi:10.1038/nrn1557