DNA structure-sensing nucleases are essential to life with roles in DNA replication, repair, and transcription. To avoid genome instability, DNA repair nucleases must precisely target the correct damaged substrate before they are licensed to incise. DNA damage identification is a challenge for all non-sequence specific DNA repair proteins, but is especially key for nucleases that cut the DNA and necessarily create a cleaved DNA repair intermediate, likely more toxic than the initial damage. How DNA repair enzymes maintain genome fidelity is one of the DNA double helix secrets missed by Watson-Crick, that is only now being illuminated though structural biology and mutational analyses. How do these enzymes achieve exquisite specificity without specific sequence recognition or, in some cases, without a non-canonical DNA nucleotide? We are investigating protein-DNA structures for nucleases involved in replication, base excision repair, mismatch repair, double strand break repair (DSBR), and telomere maintenance: apurinic/apyrimidinic endonuclease 1 (APE1), Endonuclease IV (Nfo), tyrosyl DNA phosphodiesterase (TDP2), Flap endonuclease 1 (FEN1), and Meiotic recombination 11 (Mre11). Increasingly these enzymes are employed as advanced tools for synthetic biology and as targets for cancer prognosis and interventions. Structures reveal motifs for repair nucleases and mechanisms whereby these enzymes follow the carpenter's adage: measure twice, cut once. To measure twice, we find that these nucleases act as molecular level transformers that typically reshape the DNA and sometimes themselves to achieve extraordinary specificity and efficiency.

DNA and RNA repair nucleases sculpt DNA to measure twice, cut once

248th National Meeting (2014)

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