Certain proteins essential for DNA repair are also required for transcriptional initiation by RNA polymerase II, the multisubunit enzyme that transcribes protein endoding genes. In addition, DNA lesions located on the transcribed strand of active genes are repaired more rapidly than other DNA lesions. It has therefore been proposed that RNA polymerase Ii may function to identify such lesions as it """"""""needs"""""""" the DNA. Nevertheless, a critical question remains: how does RNA polymerase II signal to the rest of the DNA repair system that it has encountered damaged DNA and that the machinery must switch from """"""""transcription mode"""""""" to """"""""repair mode""""""""? This investigator has identified novel, upper molecular weight forms of RNA polymerase II's largest subunit (Pol II LS) which are induced shortly after cells are exposed to DNA damaging agents. Preliminary studies indicate that two covalent modifications already implicated in DNA repair, ubiquitination the ADP-ribosylation, may be involved in generating the upper molecular weight forms."""""""" In vitro and in vivo approaches will be utilized to (1) determine whether the upper molecular weight forms of Pol II LS are the result of ubiquitination and/or ADP-ribosylation. (2) determine whether the modification maps tot he regulatory C-terminal domain of Pol II and (3) determine whether the subset of RNA Polymerase II molecules which get modified represent elongating molecules which have stalled at DNA lesions. Because maintaining the accuracy of DNA is a sine qua non of normal cell function and because defective DNA repair contributes to the development of cancer this topic impacts profoundly on the study of human disease.
| Lu, Yi; Luo, Zhonghui; Bregman, David B (2002) RNA polymerase II large subunit is cleaved by caspases during DNA damage-induced apoptosis. Biochem Biophys Res Commun 296:954-61 |
| Luo, Z; Zheng, J; Lu, Y et al. (2001) Ultraviolet radiation alters the phosphorylation of RNA polymerase II large subunit and accelerates its proteasome-dependent degradation. Mutat Res 486:259-74 |
| Ratner, J N; Balasubramanian, B; Corden, J et al. (1998) Ultraviolet radiation-induced ubiquitination and proteasomal degradation of the large subunit of RNA polymerase II. Implications for transcription-coupled DNA repair. J Biol Chem 273:5184-9 |
