On the move for repair

Apr 17, 2012
On the move for repair

Scientists from the Friedrich Miescher Institute for Biomedical Research have elucidated mechanisms that control DNA movement in the nucleus. They found that DNA with double-strand breaks moves more than undamaged DNA, thereby ensuring that breaks are properly repaired. Error-free double-strand break repair requires that the severed DNA finds a homologous sequence, which can serve as its repair template. Enhanced movement in the nucleus appears to facilitate the search for a proper template. Given that improperly repaired double-strand breaks can cause deleterious translocations that lead to cancer, this mechanism is important for maintaining cell integrity.

The is highly organized and several specialized sub-compartments have been described in the context of transcription. For example, in , are highly conductive to transcription, whereas other regions of the nuclear periphery facilitate . However, mechanisms that transport chromatin to these sub-nuclear control regions have been unclear.

Using quantitative fluorescence microscopy of single in live budding yeast, Susan Gasser and her team at the Friedrich Miescher Institute for addressed the mechanistic requirements for chromatin movement. Two sets of findings were published recently in Genes & Development and Nature Cell Biology. In the first study, which focused on chromatin movement in general, they found that DNA movement could occur independently of transcription elongation, although it was driven by the large ATPases that remodel chromatin during transcriptional activation.

"The localized binding of a chromatin remodeling ATPase namely INO80 on a particular genetic locus, increased the nuclear volume that the tagged locus could explore, in a manner entirely dependent on the ATPase activity of the complex," comments Gasser.

Furthermore, they found that increased chromatin movement promoted the repair of double strand breaks by homologous recombination between distant sequences. This led to the notion that double-strand breaks might specifically make use of movement within the nucleus to facilitate the homology search for repair by homologous recombination. They tested this hypothesis in their second study.

In this second study, Vincent Dion, a postdoctoral fellow in the Gasser laboratory, scored the mobility of a site-specific double-strand break. The locus clearly moved faster and was less constrained than the same undamaged locus, exploring nearly half of the nuclear volume within minutes. Dion then identified the proteins required for the increase in movement, which included proteins necessary for chromatin remodeling (a subunit of INO80), proteins critical for homologous recombination (Rad51 and Rad54) and mediators of a damage response (Mec1 and Rad9).

"These results suggest that chromatin movement promotes a rate-limiting step in homologous recombination, namely, that of homology search," comments Dion, "On the other hand, too much movement can lead to gratuitous recombination with ectopic sequences, and can generate deleterious translocations that can lead to cancer. We have also found that there are mechanisms that keep movement in check unless a genome-wide search needs to take place."

Explore further: Scientists create mouse model to accelerate research on Ebola vaccines, treatments

More information: Dion V, et al. (2012) Increased mobility of double-strand breaks requires Mec1, Rad9 and the homologous recombination machinery. Nat Cell Biol. 2012 Apr 8. doi: 10.1038/ncb2465.

Neumann FR, et al. (2012) Targeted INO80 enhances subnuclear chromatin movement and ectopic homologous recombination. Genes Dev. 2012 Feb 15;26(4):369-83. doi: 10.1101/gad.176156.111

Provided by Friedrich Miescher Institute for Biomedical Research

not rated yet

Related Stories

How cells handle broken chromosomes

Feb 13, 2009

(PhysOrg.com) -- After being recognized and initially processed by the cellular machinery, the broken chromosome is extensively scanned for homology and the break itself is later tethered to the nuclear envelope. Thus the ...

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 ...

DNA repair proteins monitored at double-strand break

May 09, 2007

Investigators at St. Jude Children's Research Hospital had a molecule’s eye view of the human cell’s DNA repair kit as it assembled on a double-strand break to link together the broken ends. Double-strand breaks are ruptures ...

Recommended for you

Researchers capture picture of microRNA in action

23 hours ago

Biologists at The Scripps Research Institute (TSRI) have described the atomic-level workings of "microRNA" molecules, which control the expression of genes in all animals and plants.

Blocking a fork in the road to DNA replication

Oct 30, 2014

A team of Whitehead Institute scientists has discovered the surprising manner in which an enigmatic protein known as SUUR acts to control gene copy number during DNA replication. It's a finding that could shed new light on ...

Cell division, minus the cells

Oct 30, 2014

(Phys.org) —The process of cell division is central to life. The last stage, when two daughter cells split from each other, has fascinated scientists since the dawn of cell biology in the Victorian era. ...

A new method simplifies the analysis of RNA structure

Oct 30, 2014

To understand the function of an RNA molecule, similar to the better-known DNA and vital for cell metabolism, we need to know its three-dimensional structure. Unfortunately, establishing the shape of an RNA ...

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.