Choosing the correct partner for DNA repair ::
Researchers at NIMR have shown in a recent paper in Cell how cells ensure that the correct chromosome is utilized for repairing broken DNA.
The genome of an organism is constantly subjected to DNA damage. Among the different types of DNA damage, the double stranded breaks (DSBs) - where both strands of the double helix are broken - are particularly harmful because they are likely to cause cell death if unrepaired.
Organisms ranging from bacteria to humans repair DSBs using an evolutionarily conserved process called homologous recombination. Key steps in homologous recombination are: (i) finding an intact piece of chromosome in the genome that contains the DNA sequence identical to the broken DNA, (ii) copying the missing DNA sequence from the intact chromosome into the broken DNA, and (iii) sealing the ends of the breaks.
The mechanics of copying missing DNA and sealing the ends are fairly well understood. In contrast, how a cell identifies the correct piece of DNA from which to initiate DSB-repair has remained elusive. The latter task is complicated by the fact that a cell carries several potential repair partners in its genome and the consequence of incorrect partner choice can be fatal.
In a recent paper published in the journal Cell, scientists in NIMR's Division of Stem Cell Biology and Developmental Genetics demonstrate that the cell does this by establishing barriers between the chromosomes that should not interact, thereby promoting preferential association between the broken ends and the correct repair partner. The paper also demonstrates that Mec1 and Tel1, the budding yeast homologs of the mammalian tumor suppressors ATM/ATR, play essential roles in recombination partner choice. Individuals carrying inactivating mutations in ATM exhibit complex clinical symptoms including an increased risk of cancer development and infertility.
Rita Cha, the lead researcher, said:
"Identifying a novel mechanism linking DNA repair and tumorigenesis is very exciting. It opens up new avenues to understanding cancer and reinforces the utility of model organisms in uncovering clinically-relevant mechanisms in higher organisms"
Original article
The research findings are published in full in:
Jesús A. Carballo, Anthony L. Johnson, Steven G. Sedgwick, and Rita S. Cha (2008)
Phosphorylation of the Axial Element Protein Hop1 by Mec1/Tel1 Ensures Meiotic Interhomolog Recombination
Cell 132, 758-70. Abstract
In the same issue of Cell there is a commentary on the article:
Neil Hunter (2008)
Hop1 and the Meiotic DNA-Damage Response
Cell 132,
731-2. Abstract
Internal links ::
[7 March 2008]