A key regulator of the DNA damage response is directly activated by the transcription factor FOXO3a - a protein known to regulate the cell cycle and cell death - according to a study published in Nature Cell Biology. The results provide crucial implications for research into ageing and cancer.
All cells are subject to the relentless bombardment with from environmental stresses that damage DNA, such as UV light, ionizing radiation and various chemicals. Mammalian cells have developed intricate systems both to repair the resulting damage and to stop the proliferation of damaged cells to allow for repair or the destruction of irreversibly damaged cells. Cells that escape these safeguards undergo genomic instability, a hallmark of cancer. Two key regulators of this DNA damage response are the FOXO family, which regulates the cell cycle and cell death, and a protein kinase known as ATM, which orchestrates the recruitment of DNA repair proteins at sites of damage. How ATM is activated by various flavours forms of DNA damage is an area of intense study.
Mickey Hu and colleagues, have now uncovered a direct connection between these two key regulators of the DNA damage response. One particular FOXO family member, FOXO3a, specifically binds to ATM, leading to its activation. Inhibition of FOXO3a blocks activation of ATM and hence the DNA damage response programme. Although it remains unclear how exactly FOXO3a is itself activated by DNA damage, these results connect two key players in this crucial safety mechanism, with implications for research into ageing and cancer.
Mickey Hu (University of Texas, Houston, TX, USA)
Abstract available online.
(C) Nature Cell Biology press release.
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