Polymerase incorporation and miscoding properties of 5-chlorouracil.
Chem Res Toxicol
; 23(4): 740-8, 2010 Apr 19.
Article
en En
| MEDLINE
| ID: mdl-20104909
Inflammation-mediated hypochlorous acid (HOCl) can damage DNA, DNA precursors, and other biological molecules, thereby producing an array of damage products such as 5-chlorouracil (ClU). In this study, we prepared and studied 5-chloro-2'-deoxyuridine (CldU) and ClU-containing oligonucleotide templates. We demonstrate that human K-562 cells grown in culture with 10 muM CldU incorporate substantial amounts of CldU without significant toxicity. When in the template, ClU residues pair with dATP but also with dGTP, in a pH-dependent manner with incorporation by human polymerase beta, avian myeloblastosis virus reverse transcriptase (AMV-RT), and Escherichia coli Klenow fragment (exo(-)) polymerase. The enhanced miscoding of ClU is attributed to the electron-withdrawing 5-chlorine substituent that promotes the formation of an ionized ClU-G mispair. When mispaired with G, ClU is targeted for removal by human glycosylases. The formation, incorporation, and repair of ClU could promote transition mutations and other forms of heritable DNA damage.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Uracilo
/
ADN Polimerasa beta
Límite:
Humans
Idioma:
En
Revista:
Chem Res Toxicol
Asunto de la revista:
TOXICOLOGIA
Año:
2010
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos