研究人員在11月在線出版的《自然—結(jié)構(gòu)和分子生物學(xué)》（Nature-Structural Molecular biology）期刊中報(bào)告說(shuō)，他們進(jìn)一步理解了健康細(xì)胞是如何處理抗癌藥物所造成的損害的,。
轉(zhuǎn)錄過(guò)程是指遺傳信息從DNA轉(zhuǎn)移到RNA的過(guò)程,，在絕大多數(shù)情況下，這一過(guò)程會(huì)產(chǎn)生一種特別的蛋白質(zhì),。由部分抗癌藥物所引發(fā)的DNA損傷會(huì)導(dǎo)致轉(zhuǎn)錄過(guò)程中RNA出錯(cuò),，產(chǎn)生可能有害于細(xì)胞的錯(cuò)誤蛋白質(zhì)。
順鉑(cisplatin)是一種常用的化學(xué)治療藥物,。Patrick Cramer和同事研究了轉(zhuǎn)錄機(jī)制如何避免由順鉑導(dǎo)致的DNA損傷,。他們發(fā)現(xiàn)，順鉑損傷會(huì)迫使轉(zhuǎn)錄過(guò)程在受到損害前停止,，這種轉(zhuǎn)錄過(guò)程的“中止”觸發(fā)了一種能移走毒性損傷的DNA修復(fù)通道,。（科學(xué)時(shí)報(bào)）
原始出處:
Nature-Structural Molecular biology
Published online: 11 November 2007; | doi:10.1038/nsmb1314
Mechanism of transcriptional stalling at cisplatin-damaged DNA
Gerke E Damsma1, 2, Aaron Alt1, Florian Brueckner1, 2, Thomas Carell1 & Patrick Cramer1, 2
1 Center for Integrated Protein Science CIPSM, Department of Chemistry and Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen-Strasse 25, 81377 Munich, Germany.
2 Gene Center Munich, Ludwig-Maximilians-Universität München, Feodor-Lynen-Strasse 25, 81377 Munich, Germany.
Correspondence should be addressed to Thomas Carell [email protected] or Patrick Cramer [email protected]
The anticancer drug cisplatin forms 1,2-d(GpG) DNA intrastrand cross-links (cisplatin lesions) that stall RNA polymerase II (Pol II) and trigger transcription-coupled DNA repair. Here we present a structure-function analysis of Pol II stalling at a cisplatin lesion in the DNA template. Pol II stalling results from a translocation barrier that prevents delivery of the lesion to the active site. AMP misincorporation occurs at the barrier and also at an abasic site, suggesting that it arises from nontemplated synthesis according to an 'A-rule' known for DNA polymerases. Pol II can bypass a cisplatin lesion that is artificially placed beyond the translocation barrier, even in the presence of a GA mismatch. Thus, the barrier prevents transcriptional mutagenesis. The stalling mechanism differs from that of Pol II stalling at a photolesion, which involves delivery of the lesion to the active site and lesion-templated misincorporation that blocks transcription.
