The O6-methylguanine lesion is a substrate for direct repair by O6-methylguanine-DNA methyltransferase (MGMT) (Pollack et al., 2006; Hegi et al., 2008; Fukushima et al., 2009; Zhang et al., 2012b). Without MGMT repair, O6-methylguanine initiates activation of mismatch repair-deficient (MMR) proteins or Rad3-related protein kinase that ultimately leads to apoptotic cell death (Caporali et al., 2004; Wang and Edelmann, 2006; Roos et al., 2007). High expression of MGMT or loss of MMR contributes significantly to TMZ resistance in many clinical cases (Pollack et al., 2006; Hegi et al., 2008; Sarkaria et al., 2008). The initiation of apoptotic signaling fails in the absence of the MMR system.