SET, a novel player in DNA repair and a potential chemotherapeutic target
The protein SET plays a key role in DNA repair and inhibits excessive DNA recombination by controlling chromatin structure through its interaction with the proteins KAP1 and HP1.
Cell Rep April 7, 2015
March 26, 2015
The team of Evi Soutoglou at IGBMC discovered the protein SET as a novel player in repair of lesions occurring at both strands of DNA. They showed that SET inhibits excessive DNA repair by recombination by controlling chromatin structure through its interaction with the proteins KAP1 and HP1. Cancerous cells where SET is over abundant have decreased capacity to repair DNA lesions and they are sensitive to chemotherapeutic agents, like derivatives of camptothecin.
These results are published March 26, 2015 in Cell Reports.
Cells experience constantly damage at their DNA from exogenous and endogenous sources that endanger genome stability. The lesions at both strands of DNA (DNA double strand breaks) are the most deleterious because they are difficult to repair and they can lead to gross chromosomal rearrangements, cellular transformation and cancer.
Cells respond to these lesions by initiating the DNA damage response (DDR), a signaling cascade which leads to the activation of cell cycle checkpoints and initiation of DNA repair. The spatial and temporal balance of the DNA repair pathways is essential to suppress mutagenic effects.
The team of Evi Soutoglou at IGBMC demonstrated for the first time that the protein SET – a multitasking protein involved in various cellular functions - plays a key role in DNA repair and inhibits excessive DNA recombination by controlling chromatin structure through its interaction with the two proteins KAP1 and HP1.
In cancer cells, SET overabundance leads to amplification of its normal function due to increased retention of KAP1 and HP1s to chromatin, causing long-term chromatin compaction and defect in DNA repair, phenomena that might contribute to the initiation of cancer. Interestingly, many cancers bear mutations in genes that control DNA repair. This defect in repair is exploited by chemotherapy, which uses agents to induce massive DNA damage that cannot be repaired by the tumor cells.
Recent reports show that SET is often overabundant in several types of cancer but its role in the initiation or progression of tumors is not understood Intriguingly, SET overexpressing cells are sensitive to chemotherapeutic agents, like derivatives of camptothecin suggesting that SET is an attractive therapeutic target for cancer therapy.