Abasic DNA structure, reactivity, and recognition.
Loss of a base in DNA, i.e., creation of an abasic site leaving a deoxyribose residue in the strand, is a frequent lesion that may occur spontaneously, or under the action of radiations and alkylating agents, or enzymatically as an intermediate in the repair of modified or abnormal bases. The abasic site lesion is mutagenic or lethal if not repaired. From a chemical point of view,the abasic site is an alkali-labile residue that leads to strand breakage through beta- and delta- elimination. Progress in the understanding of the chemistry and enzymology of abasic DNA largely relies upon the study of synthetic abasic duplexes. Several efficient synthetic methods have thus been developed to introduce the lesion (or a stable analogue) at defined position in the sequence. Physicochemical and spectroscopic examination of such duplexes, including calorimetry, melting temperature, high-field nmr and molecular modeling indicate that the lesion strongly destabilizes the duplex, although remaining in the canonical B-form with structural modifications strictly located at the site of the lesion. Probes have been developed to titrate the damage in DNA in vitro. Series of molecules have been devised to recognize specifically the abasic site, exhibiting a cleavage activity and mimicking the AP nucleases. Others have been prepared that bind strongly to the abasic site and show promise in potentiating the cytotoxic and antitumor activity of the clinically used nitrosourea (bis-chloroethylnitrosurea).
Lhomme
J
J
LEDSS, Chimie Bioorganique, UMR CNRS 5616, Université Joseph Fourier, Grenoble Cedex 9, France. Jean.L.homme@ujf-grenoble.fr
Constant
J F
JF
Demeunynck
M
M
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D020137:Base Pair Mismatch; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry / Q000494:pharmacology; D011088:DNA Ligases / Q000037:antagonists & inhibitors / Q000378:metabolism; D003854:Deoxyribonucleotides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure
D000970:Antineoplastic Agents; D018736:DNA Adducts; D003854:Deoxyribonucleotides; D004247:DNA; D011088:DNA Ligases