Error-Prone and Error-Free Translesion DNA Synthesis over Site-Specifically Created DNA Adducts of Aryl Hydrocarbons (3-Nitrobenzanthrone and 4-Aminobiphenyl)

Abstract

Aryl hydrocarbons such as 3-nitrobenzanthrone (NBA), 4-aminobiphenyl (ABP), acetylaminofluorene (AAF), benzo(a)pyrene (BaP), and 1-nitropyrene (NP) form bulky DNA adducts when absorbed by mammalian cells. These chemicals are metabolically activated to reactive forms in mammalian cells and preferentially get attached covalently to the N2 or C8 positions of guanine or the N6 position of adenine. The proportion of N2 and C8 guanine adducts in DNA differs among chemicals. Although these adducts block DNA replication, cells have a mechanism allowing to continue replication by bypassing these adducts: translesion DNA synthesis (TLS). TLS is performed by translesion DNA polymerases—Pol η, κ, ι, and ζ and Rev1—in an error-free or error-prone manner. Regarding the NBA adducts, namely, 2-(2′-deoxyguanosin-N2-yl)-3-aminobenzanthrone (dG-N2-ABA) and N-(2′-deoxyguanosin-8-yl)-3-aminobenzanthrone (dG-C8-ABA), dG-N2-ABA is produced more often than dG-C8-ABA, whereas dG-C8-ABA blocks DNA replication more strongly than dG-N2-ABA. dG-N2-ABA allows for a less error-prone bypass than dG-C8-ABA does. Pol η and κ are stronger contributors to TLS over dG-C8-ABA, and Pol κ bypasses dG-C8-ABA in an error-prone manner. TLS efficiency and error-proneness are affected by the sequences surrounding the adduct, as demonstrated in our previous study on an ABP adduct, N-(2′-deoxyguanosine-8-yl)-4-aminobiphenyl (dG-C8-ABP). Elucidation of the general mechanisms determining efficiency, error-proneness, and the polymerases involved in TLS over various adducts is the next step in the research on TLS. These TLS studies will clarify the mechanisms underlying aryl hydrocarbon mutagenesis and carcinogenesis in more detail.

Mammalian DNA Polymerase Kappa Activity and Specificity

“…Pol κ is inhibited by the major groove adducts BPDE- N 6 -dA [14], N 6 -furfuryl-dA [48], and bulky O 6 -alkyl-dG modifications [49,50]. Pol κ can replicate DNA templates containing various bulky and non-bulky lesions, such as BPDE- N 2 -dG [10,14,16,17,51,52,53,54,55], N 2 -(1-carboxyethyl)-dG [56,57], 8-oxo-dG [17], N 2 -alkyl-dG [10,58], O 2 - and some O 4 -alkyl-dT adducts [59,60,61,62], thymine glycol [45], DNA-peptide crosslinks, and intrastrand adducts and interstrand crosslinks (ICL) formed between purine bases and cisplatin [6,10,17,63,64,65,66,67,68,69,70].…”

Origin of mutations in genes associated with human glioblastoma multiform cancer: random polymerase errors versus deamination

“…The recruitment of these polymerases, which leave distinct mutation patterns are dependent on the nature of the blocking lesion. Depending on the blocking lesions, translesion synthesis (TLS) performed by Pol η, κ, ι, and ζ and Rev1 may be error-free or error-prone [43]. For abasic sites formed from depurination, TLS yields deletions and A misincorporation opposite the non-cognate lesion [44].…”

Probing the Effect of Bulky Lesion-Induced Replication Fork Conformational Heterogeneity Using 4-Aminobiphenyl-Modified DNA

“…It has been reported that compared with other cancers, the ABP-induced mutations are more evenly distributed along the p53 gene and the mutation hotspots occur through the genome with the major mutation being G to T transversion [21,22]. TLS over dG-C8-ABP in two different sequences (CCG*GAGGC and CCGGAG*GCC, G* = dG-C8-ABP), which represent codon 248 and 249 sequences of the human p53 tumor suppressor gene, respectively, has confirmed that codon 248 is a hot spot for adduct formation and G to T mutation.…”

“…The major induced mutation is a G to T transversion mutation. Translesion synthesis (TLS) over dG-C8-ABP in two different sequences (CCG*GAGGC and CCGGAG*GCC, G* = dG-C8-ABP), which represent the codon 248 and 249 sequences of the human p53 tumor suppressor gene, respectively, has confirmed that codon 248 is both a hot spot of ABP adduct formation and G to T mutation [22]. These results suggest that the efficiency of TLS over dG-C8-ABP is influenced by the surrounding DNA sequences.…”