Human cells bearing homozygous mutations in the DNA mismatch repair genes hMLH1 or hMSH2 are fully proficient in transcription-coupled nucleotide excision repair.

The transcription-coupled nucleotide excision repair (TCNER) pathway maintains genomic stability by rapidly eliminating helix-distorting DNA adducts, such as UV-induced cyclobutane pyrimidine dimers (CPDs), specifically from the transcribed strands of active genes. DNA mismatch repair (MMR) constitutes yet another critical antimutagenic pathway that removes mispaired bases generated during semiconservative replication. It was previously reported that the human colon adenocarcinoma strains HCT116 and LoVo (bearing homozygous mutations in the MMR genes hMLH1 and hMSH2, respectively), besides manifesting hallmark phenotypes associated with defective DNA mismatch correction, are also completely deficient in TCNER of UV-induced CPDs. This revealed a direct mechanistic link between MMR and TCNER in human cells, although subsequent studies have either supported, or argued against, the validity of this important notion. Here, the ligation-mediated polymerase chain reaction was used to show at nucleotide resolution that MMR-deficient HCT116 and LoVo retain the ability to excise UV-induced CPDs much more rapidly from the transcribed vs the nontranscribed strands of active genes. Moreover, relative to DNA repair-proficient counterparts, MMR-deficient cells were not more sensitive to the cytotoxic effects of UV, and displayed equal ability to recover mRNA synthesis following UV challenge. These results conclusively demonstrate that hMLH1- and hMSH2-deficient human colon adenocarcinoma cells are fully proficient in TCNER.