RNA polymerase: The most specific damage recognition protein in cellular responses to DNA damage?

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Abstract
DNA damage induces a number of cellular responses in human cells, including DNA repair, transcriptional reprogramming, delay of cell cycle progression, and apoptosis (1). The most common DNA lesions fall into two broad groups: base lesions and single- and double-strand breaks. Both types of lesions are detected by damage sensors that initiate various response reactions. A central question in understanding these responses is the identity of the damage sensor. The study by Derheimer et al. (2) in a recent issue of PNAS, together with previous studies, suggests that RNA polymerase II (RNAP II) stalled at a damaged DNA base may constitute the most specific signal for DNA repair, DNA damage checkpoints, and apoptosis (Fig. 1). We suggest that RNAP II is an ideal damage sensor because it has the highest selectivity of all known DNA damage recognition proteins. Fig. 1. RNAP II as the universal high-specificity damage sensor for three major cellular responses to bulky DNA lesions, such as the cyclobutane pyrimidine dimers induced by UV light. RNAP II arrests at a dimer site in the transcribed strand. The resulting structure recruits proteins that initiate repair, cell cycle checkpoints, or apoptosis. In general, the specificity of a sequence or a structure-specific DNA damage recognition protein is determined by the dissociation off-rate for the target relative to the dissociation off-rate for the nontarget DNA. The off-rates for the vast majority of specific DNA-binding proteins, such as repressors, activators, repair enzymes, and damage recognition proteins, bound at their target sites is in the range of 10−1 to 10−3 s−1. Although these slow off-rates provide considerable specificity, the specificity gained is compromised by the significant competition from the vast excess of undamaged or nontarget DNA. In contrast to the limitations of these direct or matchmaker recognition mechanisms (1), RNAP II, which … *To whom correspondence may be addressed. E-mail: llindsey{at}med.unc.edu or aziz_sancar{at}med.unc.edu