Trinucleotide repeat (TNR) expansion is responsible for numerous human neurodegenerative diseases. However, the underlying mechanisms remain unclear. Recent studies have shown that DNA base excision repair (BER) can mediate TNR expansion and deletion by removing base lesions in different locations of a TNR tract, indicating that BER can promote or prevent TNR expansion in a damage location–dependent manner. In this study, we provide the first evidence that the repair of a DNA base lesion located in the loop region of a CAG repeat hairpin can remove the hairpin, attenuating repeat expansion. We found that an 8-oxoguanine located in the loop region of CAG hairpins of varying sizes was removed by OGG1 leaving an abasic site that was subsequently 5′-incised by AP endonuclease 1, introducing a single-strand breakage in the hairpin loop. This converted the hairpin into a double-flap intermediate with a 5′- and 3′-flap that was cleaved by flap endonuclease 1 and a 3′-5′ endonuclease Mus81/Eme1, resulting in complete or partial removal of the CAG hairpin. This further resulted in prevention and attenuation of repeat expansion. Our results demonstrate that TNR expansion can be prevented via BER in hairpin loops that is coupled with the removal of TNR hairpins.
Minimal mimics of protein conformations
provide rationally designed
ligands to modulate protein function. The advantage of minimal mimics
is that they can be chemically synthesized and coaxed to be proteolytically
resistant; a key disadvantage is that minimization of the protein
binding epitope may be associated with loss of affinity and specificity.
Several approaches to overcome this challenge may be envisioned, including
deployment of covalent warheads and use of nonnatural residues to
improve contacts with the binding surface. Herein, we describe our
computational and experimental efforts to enhance the minimal protein
mimics with fragments that can contact undiscovered binding pockets
on Mdm2 and MdmXtwo well-studied protein partners of p53.
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