Poor base stacking at DNA lesions may initiate recognition by many repair proteins.
A fundamental question in DNA repair is how a mismatched or modified base is detected when embedded in millions to billions of normal base pairs. A survey of the literature and structural database reveals a common feature in all repair protein-DNA complexes: the DNA double helix is discontinuous at a lesion site due to base unstacking, kinking and/or nucleotide extrusion. Lesions induce destabilization and distortion of short linear DNAs, and underwinding in negatively supercoiled DNA presumably could compound the reduced stability caused by a lesion. A hypothesis is thus put forward that DNA lesion recognition occurs in two steps. Repair proteins initially recognize the weakened base stacking, and thus a flexible hinge at a DNA lesion. Sampling of flexible hinges rather than all DNA base pairs can reduce the task of finding a lesion by two to three orders of magnitude, from searching millions base pairs to thousands. After the initial encounter, a repair protein scrutinizes the shape, hydrogen bonding and electrostatic potentials of bases at the flexible hinge and dissociates if it is not a correct substrate. MutS, which has a broad range of substrates, actively dissociates from non-specific binding via an ATP-dependent proofreading mechanism. A single lesion may thus be sampled by BER, NER and MMR proteins until repaired. This proposition immediately suggests a mechanism for crosstalk between different repair and signaling pathways. It also raises the possibility that sampling of a lesion by one protein could facilitate loading of another by direct protein-protein or DNA mediated interactions.
Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Wei.Yang@nih.gov
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D000255:Adenosine Triphosphate / Q000737:chemistry; D001426:Bacterial Proteins / Q000737:chemistry; D020137:Base Pair Mismatch; D018360:Crystallography, X-Ray; D004249:DNA Damage; D045647:DNA Glycosylases / Q000737:chemistry; D004260:DNA Repair; D004278:DNA, Superhelical / Q000737:chemistry; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry; D006860:Hydrogen Bonding; D008968:Molecular Conformation; D051719:MutS DNA Mismatch-Binding Protein / Q000737:chemistry; D009690:Nucleic Acid Conformation; D015398:Signal Transduction; D055672:Static Electricity
D001426:Bacterial Proteins; D004278:DNA, Superhelical; D000255:Adenosine Triphosphate; D004259:DNA-Directed DNA Polymerase; D045647:DNA Glycosylases; D051719:MutS DNA Mismatch-Binding Protein