Strand specific recognition of DNA damages by XPD provides insights into Nucleotide Excision Repair substrate versatility [Molecular Biophysics]

December 14th, 2013 by Buechner, C. N., Heil, K., Michels, G., Carell, T., Kisker, C., Tessmer, I.

Recognition and removal of DNA damages is essential for cellular and organismal viability. Nucleotide excision repair (NER) is the sole mechanism in humans for the repair of carcinogenic UV irradiation induced photoproducts in the DNA, such as cyclobutane pyrimidine dimers (CPDs). The broad substrate versatility of NER further includes, amongst others, various bulky DNA adducts. It has been proposed that the 5′-3′ helicase Xeroderma pigmentosum group D protein (XPD) plays a decisive role in damage verification. However, in spite of recent advances such as the identification of a DNA binding channel and central pore in the protein, through which the DNA is threaded, as well as a dedicated lesion recognition pocket near the pore, the exact process of target site recognition and verification in eukaryotic NER still remained elusive. Our single molecule analysis by atomic force microscopy reveals for the first time that XPD utilizes different recognition strategies to verify structurally diverse lesions. A bulky fluorescein damage is preferentially detected on the translocated strand, while the opposite strand preference is observed for a CPD lesion. Both states, however, lead to similar conformational changes in the resulting specific complexes indicating a merge to a ″final″ verification state, which may then trigger the recruitment of further NER proteins.
  • Posted in Journal of Biological Chemistry, Publications
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