Differential involvement of the human mismatch repair proteins, hMLH1 and hMSH2, in transcription-coupled repair

Abstract

Defects in DNA mismatch repair have been associated with both hereditary and sporadic forms of cancer. Recently, it has been shown that human cell lines deficient in mismatch repair were also defective in the transcription-coupled repair (TCR) of UV-induced DNA damage. We examined whether TCR of ionizing radiation-induced DNA damage also requires the genes involved in DNA mismatch repair. Cells defective in the hMSH2 gene were deficient in the removal of oxidative damage, including thymine glycols, from the transcribed strand of an active gene. However, an hMLH1 mutant showed normal levels of TCR. By comparison, defects in either hMSH2 or hMLH1 resulted in reduced TCR of UV damage. Introducing chromosomes carrying either hMSH2 or hMLH1 into these cell lines restored their ability to carry out TCR. Deficiencies in either hMSH2 or hMLH1 did not result in decreased overall genomic levels of repair or lead to an increased sensitivity to either UV or ionizing radiation. Our results provide the first evidence for a protein that is absolutely required for the preferential removal of UV-induced DNA damage but not oxidative DNA damage from the transcribed strand of an active human gene.