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A key interaction with RPA orients XPA in NER complexes

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Title
A key interaction with RPA orients XPA in NER complexes
Author(s)
Topolska-Wos A.M.; Sugitani N.; Cordoba J.J.; Le Meur K.V.; Le Meur R.A.; Hyun Suk Kim; Jung-Eun Yeo; Rosenberg D.; Hammel M.; Orlando D. Sch¨arer; Chazin W.J.
Publication Date
2020-02
Journal
NUCLEIC ACIDS RESEARCH, v.48, no.4, pp.2173 - 2188
Publisher
OXFORD UNIV PRESS
Abstract
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.The XPA protein functions together with the single-stranded DNA (ssDNA) binding protein RPA as the central scaffold to ensure proper positioning of repair factors in multi-protein nucleotide excision repair (NER) machinery. We previously determined the structure of a short motif in the disordered XPA N-terminus bound to the RPA32C domain. However, a second contact between the XPA DNA-binding domain (XPA DBD) and the RPA70AB tandem ssDNA-binding domains, which is likely to influence the orientation of XPA and RPA on the damaged DNA substrate, remains poorly characterized. NMR was used to map the binding interfaces of XPA DBD and RPA70AB. Combining NMR and X-ray scattering data with comprehensive docking and refinement revealed how XPA DBD and RPA70AB orient on model NER DNA substrates. The structural model enabled design of XPA mutations that inhibit the interaction with RPA70AB. These mutations decreased activity in cell-based NER assays, demonstrating the functional importance of XPA DBD-RPA70AB interaction. Our results inform ongoing controversy about where XPA is bound within the NER bubble, provide structural insights into the molecular basis for malfunction of disease-associated XPA missense mutations, and contribute to understanding of the structure and mechanical action of the NER machinery
URI
https://pr.ibs.re.kr/handle/8788114/7175
ISSN
0305-1048
Appears in Collections:
Center for Genomic Integrity(유전체 항상성 연구단) > Journal Papers (저널논문)
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