EuroDYNA takes lid off the genome

[Guest guest]

EuroDYNA takes lid off the genome

http://www.eurekalert.org/pub_releases/2008-06/esf-etl061308.php

European researchers have made significant progress unravelling how

genes are governed and why this sometimes goes wrong in disease. The

key lies in the dynamic ever-changing structure of the chromatin,

which is the underlying complex of protein and DNA making up the

chromosomes in which almost all genes are housed within the genome.

The way this structure changes and responds to external signalling

molecules within the cell determines how and when genes are expressed

and also the mechanisms used to repair DNA damaged by a variety of

internal and external insults, such as ultra violet radiation and

free radical by-products of metabolism.

Understanding the structure of chromatin and its interactions with

proteins and RNA within the cell was the goal of the European Science

Foundation's (ESF) EuroDYNA programme, which held its last conference

at the Wellcome Trust Conference Centre near Cambridge in May 2008.

The study of genome structure involves interaction between various

disciplines including cell biology, molecular physics, biomechanics

and bioinformatics, as well as access to a wide range of expensive

equipment such as electron microscopes, supercomputers, and scanners

for simultaneous profiling of RNA expression across the whole genome.

EuroDYNA helped broker these collaborations and enable projects to

develop the critical mass needed to make real progress.

The expression of genes involves an apparatus comprised mostly of

proteins for reading the DNA, leading to production of RNA. This RNA

in turn is either transported within the cell to the protein factory

called the ribosome, where the code is translated into proteins, or

else it interacts with other genes to control their expression in

turn. These processes are intimately related to the constantly

changing physical and chemical structure of the chromatin.

Furthermore the overall state of the genome evolves during the life

cycle of the cell, leading to its duplication if and when the cell

eventually divides. All these inter-related processes need to be

understood in order to unravel the complex network of mechanisms

controlling gene expression.

One of the big fundamental questions tackled within EuroDYNA

concerned the detailed structure of how the DNA double helix is

folded in the nucleus of higher organisms. Although the double helix

structure was discovered by Crick and in 1953, the way it

folds and stretches such that it fits in the cell nucleus is only now

becoming clear, as is its relevance both for cell replication and

gene expression. At the EuroDYNA conference, van Noort from

Leiden University in the Netherlands reported that the DNA molecule,

which in humans and most mammals is about two metres in length but

only 2 nanometres in diameter, is coiled up like a spring in a

solenoid structure. In such a folded structure it behaves according

to the well known Hooke's law, stating that up to a certain point the

extension is proportional to the force applied. It turns out

chromatin is a very elastic molecular complex, capable of stretching

to three times its normal rest length without breaking, according to

van Noort. Even more remarkably – and here it differs from a familiar

metal spring - even if stretched beyond three times its rest length,

the chromatin solenoid is capable of repairing itself and regaining

its former shape and elasticity.

Indeed the ability of DNA to repair itself is essential for the long

term survival of the cell and ultimately of the whole organism. DNA

damage occurs not just from factors outside the cell nucleus, but

also during the process of cell division (mitosis). The overall

objective is to hand down the correct genetic code to the daughter

cells during mitosis, a process so important that a number of

surveillance and repair systems have been put in place to ensure its

completion. One of those systems is called PRR (Post Replicative

Repair) and it is highly conserved among all organisms, from bacteria

to eukarya. PRR was discovered in the 1970s, but here again the

detailed mechanisms are only now being elicited. At the EuroDYNA

conference, Simone Sabbioneda from the University of Sussex presented

new findings about one of the key PRR mechanisms called Translesion

DNA Synthesis (TLS). This project, like some of the others, involved

direct observation of processes as they take place in living cells,

in this case using a technique called Fluorescence Recovery after

Photobleaching. This comprises an optical microscope combined with a

probe to observe the radiation emitted (the fluorescence) by

molecules within a cell in response to a laser source. Such work is

yielding important clues on how the PRR pathways work, hoping to help

in the long term campaign to find novel, more specific, treatments

for cancer, without the side effects of current therapies based on

surgery, radiotherapy, or chemotherapy.

One EuroDYNA project however yielded a more immediate insight into a

treatment already used to alleviate the symptoms of another important

disease, MS (multiple sclerosis). Pavel Kovarik from the University

of Vienna's Department of Microbiology and Immunology noted that the

only compound capable of alleviating MS symptoms was the protein

interferon beta. This resembles the interferon produced naturally by

the body in response to infection, but until now it has not been

known how it relieves symptoms for MS sufferers. However Kovarik and

colleagues have shown that interferon works by upregulating

(increasing production of) members of the protein family

Tristetraprolin (TTP), which have an anti-inflammatory affect by in

turn inhibiting production of pro-inflammatory agents. " We have

demonstrated a novel function for interferon, " said Kovarik. By

understanding how it works, there is the potential for delivering

interferon beta more effectively for treating MS.

There were other projects within EuroDYNA with great therapeutic

potential, many of which will continue, but which would benefit

greatly from an extension to this highly successful programme.