A splice of life - Groundbreaking study reveals intermediary steps of genetic en

[Guest guest]

A splice of life

Groundbreaking study reveals intermediary steps of genetic encoding for the

first time

http://www.eurekalert.org/pub_releases/2009-03/bu-aso032709.php

In a new study this week in Nature, researchers at Brandeis University and the

MRC Laboratory of Molecular Biology (Cambridge, U.K.) for the first time shed

light on a crucial step in the complex process by which human genetic

information is transmitted to action in the human cell and frequently at which

point genetic disease develops in humans.

The scientists report that they were able to crystallize a very large complex of

a macromolecular " machine " in the human cell and determine its structure or what

it actually looks like, thereby zeroing in on the process of genetic encoding.

Importantly, 15 to 20 percent of all human genetic disorders, including muscular

dystrophy, are caused by defects in this genetic encoding process known as RNA

splicing.

Using x-ray crystallography, the scientists for the first time were able to

create a three-dimensional structure of an integral complex of the human

spliceosome, which consists of specialized RNA and protein subunits. The

spliceosome's job is to modify the message relayed from our genetic

material—DNA—by clipping, or splicing, genetic bits in such a manner that they

are acceptable for translation into protein. Importantly, the spliceosome also

rearranges the genetic bits of the message in such a way that it can generate

multiple and varied proteins which can and do have dramatic effects on human

development, said lead author and Brandeis biochemist Pomeranz Krummel.

" The process of RNA splicing is vital to human cell development and survival, "

said Pomeranz Krummel. " In this process, the regions of our DNA encoding for

protein are removed from non-encoding regions and brought together—quite often

in alternative arrangements. Defects in this process can have disasterous

repercussions in the form of genetic disorders, " said Pomeranz Krummel, adding

that neuronal development can be particularly affected when things go awry.

Indeed, defects in this process have recently been implicated in various human

neurological disorders, including epilepsy.

Specifically, this macromolecular machine clips, or splices, gene sequences

transcribed as part of a precursor to the mRNA, removing them before the final

mRNA product is translated into protein. The spliceosome must clip these

sequences, known as introns, at the right place in the precursor mRNA.

" In human cells one gene can be made into a variety of proteins, so if the

process just goes slightly wrong, the genetic alteration can lead to incredible

disaster; yet on the other hand, this incredible complexity has led to our

amazing evolutionary progress, " said Pomeranz Krummel. " The human genome is not

terribly different from the earthworm's with regards to its size, but the

process of RNA splicing that occurs in our cells is different. The fundamental

difference between us and the earthworm is that our cells have evolved to

utilize this process of RNA splicing to generate a whole other dimension to the

transmission of genetic information. "

Pomeranz Krummel's lab will next focus on understanding how this complex

interacts with other macromolecular machines in the human cell. The study was

funded by the Medical Research Council (U.K.) and the Human Frontier Science

Program.