TY - JOUR
T1 - Differential Nucleotide Excision Repair Susceptibility of Bulky DNA Adducts in Different Sequence Contexts
T2 - Hierarchies of Recognition Signals
AU - Cai, Yuqin
AU - Patel, Dinshaw J.
AU - Geacintov, Nicholas E.
AU - Broyde, Suse
N1 - Funding Information:
This work was supported by the National Cancer Institute, National Institutes of Health, through grants CA28038 (S.B.), CA099194 (N.E.G.), and CA046533 (D.J.P). Partial support for computational infrastructure and systems management was also provided by grant CA75449 (S.B.). The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.
PY - 2009/1/9
Y1 - 2009/1/9
N2 - The structural origin underlying differential nucleotide excision repair (NER) susceptibilities of bulky DNA lesions remains a challenging problem. We investigated the 10S (+)-trans-anti-[BP]-N2-2′-deoxyguanosine (G*) adduct in double-stranded DNA. This adduct arises from the reaction, in vitro and in vivo, of a major genotoxic metabolite of benzo[a]pyrene (BP), (+)-(7R,8S,9S,10R)-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, with the exocyclic amino group of guanine. Removal of this lesion by the NER apparatus in cell-free extracts has been found to depend on the base sequence context in which the lesion is embedded, providing an excellent opportunity for elucidating the properties of the damaged DNA duplexes that favor NER. While the BP ring system is in the B-DNA minor groove, 5′ directed along the modified strand, there are orientational distinctions that are sequence dependent and are governed by flanking amino groups [Nucleic Acids Res. 35 (2007), 1555-1568]. To elucidate sequence-governed NER susceptibility, we conducted molecular dynamics simulations for the 5′-...CG*GC..., 5′-...CGG*C..., and 5′-...TCG*CT... adduct-containing duplexes. We also investigated the 5′-...CG*IC... and 5′-...CIG*C... sequences, which contain "I" (2′-deoxyinosine), with hydrogen replacing the amino group in 2′-deoxyguanosine, to further characterize the structural and dynamic roles of the flanking amino groups in the damaged duplexes. Our results pinpoint explicit roles for the amino groups in tandem GG sequences on the efficiency of NER and suggest a hierarchy of destabilizing structural features that differentially facilitate NER of the BP lesion in the sequence contexts investigated. Furthermore, combinations of several locally destabilizing features in the hierarchy, consistent with a multipartite model, may provide a relatively strong recognition signal.
AB - The structural origin underlying differential nucleotide excision repair (NER) susceptibilities of bulky DNA lesions remains a challenging problem. We investigated the 10S (+)-trans-anti-[BP]-N2-2′-deoxyguanosine (G*) adduct in double-stranded DNA. This adduct arises from the reaction, in vitro and in vivo, of a major genotoxic metabolite of benzo[a]pyrene (BP), (+)-(7R,8S,9S,10R)-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, with the exocyclic amino group of guanine. Removal of this lesion by the NER apparatus in cell-free extracts has been found to depend on the base sequence context in which the lesion is embedded, providing an excellent opportunity for elucidating the properties of the damaged DNA duplexes that favor NER. While the BP ring system is in the B-DNA minor groove, 5′ directed along the modified strand, there are orientational distinctions that are sequence dependent and are governed by flanking amino groups [Nucleic Acids Res. 35 (2007), 1555-1568]. To elucidate sequence-governed NER susceptibility, we conducted molecular dynamics simulations for the 5′-...CG*GC..., 5′-...CGG*C..., and 5′-...TCG*CT... adduct-containing duplexes. We also investigated the 5′-...CG*IC... and 5′-...CIG*C... sequences, which contain "I" (2′-deoxyinosine), with hydrogen replacing the amino group in 2′-deoxyguanosine, to further characterize the structural and dynamic roles of the flanking amino groups in the damaged duplexes. Our results pinpoint explicit roles for the amino groups in tandem GG sequences on the efficiency of NER and suggest a hierarchy of destabilizing structural features that differentially facilitate NER of the BP lesion in the sequence contexts investigated. Furthermore, combinations of several locally destabilizing features in the hierarchy, consistent with a multipartite model, may provide a relatively strong recognition signal.
KW - GG mutation hotspot
KW - benzo[a]pyrenyl-guanine lesion
KW - guanine amino group
KW - nucleotide excision repair susceptibility
KW - sequence-dependent conformational variability
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U2 - 10.1016/j.jmb.2008.09.087
DO - 10.1016/j.jmb.2008.09.087
M3 - Article
C2 - 18948114
AN - SCOPUS:57749188239
SN - 0022-2836
VL - 385
SP - 30
EP - 44
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 1
ER -