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. Author manuscript; available in PMC: 2021 Jun 15.
Published in final edited form as: Toxicol Lett. 2020 Mar 12;326:78–82. doi: 10.1016/j.toxlet.2020.03.008

Fig. 1. Summary of DNA damage signaling following exposure of cells to vesicants.

Fig. 1.

Mustard vesicants cause DNA damage forming both signal-strand breaks (SSBs) and double-strand breaks (DSBs). In response, cells activate DNA damage response (DDR) signaling pathways. This is initiated by DNA damage sensors such as ATRIP (ATR interacting protein), MRN (MRE11–RAD50–NBS1) complex and the Ku70/Ku80 complex. These proteins are recruited to sites of DNA damage where they trigger DNA damage signaling transducers, including apical phosphatidylinositol 3-kinase-related kinases (PIKKs) such as ATM, ATR, and DNA-PKcs. ATM and DNA-PKcs respond to DNA double strand breaks, while ATR responds to replication protein A (RPA)-coated single strand DNA (ssDNA). These are activated by phosphorylation. ATR and ATM activate downstream cell cycle regulators CHK1 and CHK2, respectively, which in turn signals downstream regulatory proteins such as p53 to regulate cell cycle transit and to activate DNA repair, apoptosis and/or senescence. Activated PIKKs also phosphorylate H2AX, a histone H2A variant, at S139 to promote DNA repair.