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DNA Damage Response Research, Inherent and Future Nano-Based Interfaces for Personalized Medicine
Published in Yubing Xie, The Nanobiotechnology Handbook, 2012
Madhu Dyavaiah, Lauren Endres, Yiching Hsieh, William Towns, Thomas J. Begley
Single- and double-strand breaks can be caused by ionizing radiation, alkylating agents, reactive oxygen species (ROS), and as the by-products of DNA replication and repair. Failure to repair single- or double-strand breaks can promote mutations, chromosomal instability, and cell death. The first step in the repair of strand breaks is the identification of said break. Two well-known DNA damage sensors—Mre11-Rad50-Nbs1 (MRN) and Rad9-Rad1-Hsu1 (9-1-1) complexes (Figure 6.1)—respond to double- or single-strand breaks (Lee and Paull 2005, Parrilla-Castellar et al. 2004). The highly conserved MRN complex plays a critical role in sensing double-strand breaks, triggering the signaling pathway, facilitating DNA repair and providing the maintenance of telomere integrity and meiosis (van den Bosch et al. 2003, Williams et al. 2007). Mre11, which has 3′ to 5′ dsDNA exonuclease activity and ssDNA endonuclease activity, binds to DNA, Rad50, and Nbs1 through its coiled-coil regions (Hopfner et al. 2002). Nbs1 interacts with Mre11 and acts as a flexible adaptor of the MRN complex, regulating and recruiting signal-transduction kinases to DNA lesions (Carney et al. 1998, Lee and Paull 2005). Damage recognition by the MRN complex is ATP-dependent. The presence of ATP at the damage site catalyzes a series of conformational changes. One example of such a change was revealed by crystal analysis of Mre11-Rad50 bound to ATP/ADP. The presence of ATP allows the Rad50 nucleotide-binding domains to shift closer to the Mre11 nuclease and binding sites. The shift allows for increased binding to dsDNA. This complex has the estimated dimensions of 7.5 × 8.0 × 9.2 nm (Mockel et al. 2012). Mre11-Rad50 dimers have been shown to bring DNA ends within 10 nm of each other for repair (Chen et al. 2001, Hopfner et al. 2002). The DNA–Mre11 interaction has been recently studied using crystallography. All six DNA-binding domains interact with the sugar-phosphate backbone of dsDNA, allowing for a general synapse between the Mre11, while Rad50 is required to bridge the DNA ends (Williams et al. 2008).
Impact of stainless-steel welding fumes on proteins and non-coding RNAs regulating DNA damage response in the respiratory tract of Sprague-Dawley rats
Published in Journal of Toxicology and Environmental Health, Part A, 2018
Jayaraman Krishnaraj, Abdul Basit Baba, Periasamy Viswanathan, Veeran Veeravarmal, Viswalingam Balasubramanian, Siddavaram Nagini
ATM, a key player that orchestrates DDR, undergoes autophosphorylation at Ser1981 in response to DSBs, triggering phosphorylation of over 700 target proteins including those involved in DDR, such as p53, a master regulator of genomic stability (Laptenko and Prives 2017; Shiloh and Ziv 2013). Phosphorylation of Nbs1 by ATM promotes HR, a critical determinant of DSB repair pathway choice (Kowalczykowski 2015). ATM directly phosphorylates the MRN-interacting protein CtIP, a key nuclease required for resection initiation (Wang et al. 2013), prompting the removal of Ku from single-ended DSB ends to enable HR to proceed over NHEJ (Britton, Coates, and Jackson 2013). ATM also activates NHEJ by phosphorylating 53BP1 at Ser25 (Harding, Coackley, and Bristow 2011). In addition, ATM phosphorylates BRCA1 that promotes error-free HR at the expense of 53BP1-mediated error-prone NHEJ (Hustedt and Durocher 2016). It is possible that phosphorylation of ATM by welding fumes triggers a cascade of phosphorylation and activation of multiple proteins involved in HR and NHEJ. While phosphorylation of BRCA1, Mre11 and Nbs1 with upregulation of Rad50 confirms activation of HR, overexpression of 53BP1, DNA-PKcs, Ku80 and XLF indicates NHEJ activation. Most importantly, phosphorylation of the histone variant, H2AX at Ser139 by ATM essential for recruiting DDR factors to damaged chromatin formation of MRN, BRCA1, and 53BP1 foci may play acritical role in welding fume-induced DDR.