We hypothesized that acquired deficiencies in ATM and/or MRE11 would lead to a dysfunctional repair mechanism and an inability to restore genomic stability, resulting in increased tumor cell death following radiotherapy. At least in the relatively small, but well characterized subgroup of microsatellite unstable CRCs with deficiencies in DNA mismatch repair (MMR) proteins, the accumulation of errors during replication and recombination  presents a mechanism for inactivation of ATM and MRE11 through function-ablating mutations. As a corollary, we proposed that ATM and MRE11 might be used as a predictive marker of radiosensitivity in rectal cancer patients, which would correlate with improved patient outcomes.