8-(Hydroxymethyl)-3,N⁴-etheno-C, a Potential Carcinogenic Glycidaldehyde Product, Miscodes In Vitro Using Mammalian DNA Polymerases

Abstract

, is a mutagen and animal carcinogen resulting from the reaction of dC with glycidaldehyde. It was synthesized and its phosphoramidite was incorporated site-specifically into a defined 25-mer oligonucleotide. In this study the mutagenic potential of this compound was investigated

Basis of Miscoding of the DNA Adduct N2,3-Ethenoguanine by Human Y-family DNA Polymerases

“…Compared with pol and pol , the higher activity of pol copying past N 2 ,3-⑀G observed here is similar to that seen previously for other etheno adducts, i.e. 1,N 2 -⑀G (29), 1,N 6 -⑀A (26,49), and 3,N 4 -⑀C (50). With regard to DNA polymerases, the extension pattern is particularly similar to that of bypass of 1,N 2 -⑀G; i.e.…”

“…Similarly, pol copied past 1,N 6 -⑀A in the order of preference T Ͼ C Ͼ A Ͼ G (49). The order was G Ͼ A Ͼ C for 1,N 2 -⑀G (29) and A Ϸ G Ͼ C Ϸ T for 3,N 4 -⑀C (50). Pol has the highest misincorporation frequency (although C is preferred 1.5-fold compared with T), which is consistent with the view that pol generally catalyzes errorprone bypass (3).…”

Miscoding properties of 1,N6-ethanoadenine, a DNA adduct derived from reaction with the antitumor agent 1,3-bis(2-chloroethyl)-1-nitrosourea

“…Studies using in vitro replication systems have revealed that the three related Y family enzymes, pols η (Rad30A), ι (Rad30B) and κ (DinB1), are capable of bypassing various DNA lesions [e.g. [28][29][30][31][32][33][34][35][36] that are normally blockers of classical DNA polymerases such as pol α and pol β. However, such translesion syntheses can be error-free or error-prone.…”

Translesion Synthesis across Bulky N2-Alkyl Guanine DNA Adducts by Human DNA Polymerase κ

“…The ability of pol to bypass a number of types of DNA damage has been reported, including guanine modified with N-acetylaminofluorene or BPDE (9 -14), xanthine (15), 8-nitroguanine (16), and guanine modified with oxidized estrogens (17). However, pol has not been judged to be very efficient in bypassing UV photoproducts (9,18), cis-platin-modified DNA (10), 1,N 6 -ethenodeoxyadenine (19), O 6 -MeG (20), or 8-(hydroxymethyl)-3,N 4 -ethenoC (21). Other issues involving pol include up-regulation in lung cancer (22), a possible (but not established) role in somatic hypermutation (23), and a general role in genome maintenance versus instability (24).…”