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Flipping of alkylated DNA damage bridges base and nucleotide excision repair

Julie L Tubbs1, Vitaly Latypov, Sreenivas Kanugula

  • 1Skaggs Institute for Chemical Biology and Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.

Nature
|June 12, 2009
PubMed

Insights

Alkyltransferase-like proteins (ATLs) protect cells from DNA alkylation damage without enzymatic activity. Structural studies reveal ATLs interact with damaged DNA, linking base damage processing to nucleotide excision repair pathways across life.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Genetics

Background:

  • Alkyltransferase-like proteins (ATLs) share motifs with O(6)-alkylguanine-DNA alkyltransferase (AGT) but lack its DNA repair activity.
  • ATLs paradoxically protect cells from DNA alkylation damage, a mechanism not fully understood.

Purpose of the Study:

  • To elucidate the structural basis of ATL interactions with alkylated DNA.
  • To understand the evolutionary origins and functional connections of ATLs in DNA repair.

Main Methods:

  • X-ray crystallography of Schizosaccharomyces pombe ATL with damaged DNA.
  • Bioinformatic analysis of lesion-binding site conservation.
  • Genetic and biochemical interaction studies with DNA repair proteins.

Main Results:

  • Determined structures of ATLs bound to O(6)-methylguanine and O(6)-4-(3-pyridyl)-4-oxobutylguanine.
  • Revealed non-enzymatic DNA nucleotide flipping, increased DNA distortion, and larger binding pockets compared to AGT.
  • Identified conserved ATL homologs in diverse organisms, suggesting ancient origins.
  • Demonstrated connections between ATLs and nucleotide excision repair pathways.

Conclusions:

  • ATLs sculpt alkylated DNA, creating a structural and genetic intersection between base damage processing and nucleotide excision repair.
  • ATL interactions represent an ancestral DNA repair mechanism conserved across all domains of life.

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