DNA breaks : stop to better repair
When DNA double strands breaks occur, the DNAPK stops all transcription activity in order to repair the damaged DNA chip.
Nat Struct Mol Biol Feb. 12, 2012
Feb. 12, 2012
DNA double-strand breaks are particularly dangerous as they can lead to cancer. Evi Soutoglou's team from the French Institute of Genetics and Molecular and Cellular biology (IGBMC, Strasbourg) has just deciphered mechanisms that prevent the expression of genetic information when it is damaged. They have brought to light a novel role of a protein, the DNA-dependent protein kinase, in this process. These results are published on February 12th in Nature Structural & Molecular Biology.
DNA and its lesions
Our genetic information sets on DNA and is formed of a double-strand helix. This helix is regularly attacked by environmental and metabolic factors that can lead to breaks. These damages may just occur on one strand and can be easily repaired. On the other hand, breaks affecting both strands are very deleterious: more difficult to be repaired, they can spark off chromosomal translocations (reorganization of fragments of chromosomes) and lead to cancers. Many biological mechanisms are able to detect breaks and stop ongoing nuclear processes until the breaks are repaired but they are not entirely deciphered yet.
Transcription blockade on DNA breaks
Regularly, DNA is « read » by an enzyme, the RNA polymerase II: this is the transcription process, one of the first steps of protein synthesis. Consequences on transcription and RNA polymerase II when the DNA molecule is broken were not well understood. Evi Soutoglou’s team at IGBMC has focused on this problem. Researchers used an enzyme, the endonuclease I-Ppol, able to cause double-strand breaks on targeted regions, allowing a precise analyze of the transcriptional activity on these areas. They showed that one double-strand break was leading to a total blockade of transcription of the genes affected by the break. They notably underlined the key role of the DNA-dependent protein kinase (DNAPK). Indeed, when this protein is inactivated, the RNA polymerase II is not blocked: it bypasses the break and goes on its transcriptional activity. The role of DNAPK in preventing RNA Pol II bypassing a double strand break might be key in avoiding the production of mutated transcripts that could give rise to cancerous phenotypes.