CH391L/S2013 Logan R Myler Jan 30 2013

Review of "Activation of the Cellular DNA Damage Response in the Absence of DNA Lesions" by Soutoglou and Misteli.

Background

DNA Double Strand Breaks (DSBs) can occur from a variety of both endogenous and exogenous insults, including radiation, stalled replication machinery, and reactive oxygen species (ROS). The reaction of the cell to such breaks involves a multi-step recruitment of proteins known as the DNA Damage Response (DDR). These proteins form distinct nuclear foci by localizing to the break, which can lead to halting of the cell cycle, resection, and if necessary apoptosis. (1) This has been shown to be initiated by the binding of the Mre11-Rad50-Nbs1 (MRN) complex to ends and the activation of the Ataxia-Telangiectasia Mutated (ATM) kinase. (2) Activated ATM phosphorylates a histone variant H2AX, leading to the accumulation of three mediator proteins: BRCA1, 53BP1, and MDC1, which facilitate the recruitment of other factors. It is not known what the role the localization of so many repair factors is, but the abrogation of this accumulation prohibits the DNA Damage Response. The downstream phosphorylation of checkpoint kinases Chk1 and Chk2 by ATR (Ataxia-Telangiectasia and Rad3-related) kinase and ATM respectively halt the cell cycle in G2/M, allowing the cell to repair the broken DNA.

References

1. Soutoglou, E. and Misteli, T. (2008). "Activation of the Cellular DNA Damage Response in the Absence of DNA Lesions". Science. 320: 1507-1510.
2. Bekker-Jensen S., et al. (2006). "Spatial organization of the mammalian genome surveillance machinery in response to DNA strand breaks." The Journal of Cell Biology. 173:195.
3. Lee, J.-H. and Paull, T.T. (2004). "The Mre11/Rad50/Nbs1 complex directly promotes ATM kinase activity". Science 304: 93-96.