10.1021/bi201794x.s009
Yuqin Cai
Yuqin
Cai
Nicholas
E. Geacintov
Nicholas
E.
Geacintov
Suse Broyde
Suse
Broyde
Nucleotide Excision Repair
Efficiencies of Bulky Carcinogen–DNA
Adducts Are Governed by a Balance between Stabilizing and Destabilizing
Interactions
American Chemical Society
2012
PAH
Destabilizing InteractionsThe nucleotide excision repair
DNA lesions
Nucleotide Excision Repair Efficiencies
diol epoxide metabolites
NER efficiencies
mutagenic DNA adducts
2012-02-21 00:00:00
Media
https://acs.figshare.com/articles/media/Nucleotide_Excision_Repair_Efficiencies_of_Bulky_Carcinogen_DNA_Adducts_Are_Governed_by_a_Balance_between_Stabilizing_and_Destabilizing_Interactions/2548057
The nucleotide excision repair (NER) machinery, the primary
defense
against cancer-causing bulky DNA lesions, is surprisingly inefficient
in recognizing certain mutagenic DNA adducts and other forms of DNA
damage. However, the biochemical basis of resistance to repair remains
poorly understood. To address this problem, we have investigated a
series of intercalated DNA–adenine lesions derived from carcinogenic
polycyclic aromatic hydrocarbon (PAH) diol epoxide metabolites that
differ in their response to the mammalian NER apparatus. These stereoisomeric
PAH-derived adenine lesions represent ideal model systems for elucidating
the effects of structural, dynamic, and thermodynamic properties that
determine the recognition of these bulky DNA lesions by NER factors.
The objective of this work was to gain a systematic understanding
of the relation between aromatic ring topology and adduct stereochemistry
with existing experimental NER efficiencies and known thermodynamic
stabilities of the damaged DNA duplexes. For this purpose, we performed
100 ns molecular dynamics studies of the lesions embedded in identical
double-stranded 11-mer sequences. Our studies show that, depending
on topology and stereochemistry, stabilizing PAH–DNA base van
der Waals stacking interactions can compensate for destabilizing distortions
caused by these lesions that can, in turn, cause resistance to NER.
The results suggest that the balance between helix stabilizing and
destabilizing interactions between the adduct and nearby DNA residues
can account for the variability of NER efficiencies observed in this
class of PAH–DNA lesions.