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Recognition of DNA damage by the Rad4 nucleotide excision repair protein

Author

Listed:
  • Jung-Hyun Min

    (Structural Biology Program and,)

  • Nikola P. Pavletich

    (Structural Biology Program and,
    Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA)

Abstract

Mutations in the nucleotide excision repair (NER) pathway can cause the xeroderma pigmentosum skin cancer predisposition syndrome. NER lesions are limited to one DNA strand, but otherwise they are chemically and structurally diverse, being caused by a wide variety of genotoxic chemicals and ultraviolet radiation. The xeroderma pigmentosum C (XPC) protein has a central role in initiating global-genome NER by recognizing the lesion and recruiting downstream factors. Here we present the crystal structure of the yeast XPC orthologue Rad4 bound to DNA containing a cyclobutane pyrimidine dimer (CPD) lesion. The structure shows that Rad4 inserts a β-hairpin through the DNA duplex, causing the two damaged base pairs to flip out of the double helix. The expelled nucleotides of the undamaged strand are recognized by Rad4, whereas the two CPD-linked nucleotides become disordered. These findings indicate that the lesions recognized by Rad4/XPC thermodynamically destabilize the Watson–Crick double helix in a manner that facilitates the flipping-out of two base pairs.

Suggested Citation

  • Jung-Hyun Min & Nikola P. Pavletich, 2007. "Recognition of DNA damage by the Rad4 nucleotide excision repair protein," Nature, Nature, vol. 449(7162), pages 570-575, October.
    • Handle: RePEc:nat:nature:v:449:y:2007:i:7162:d:10.1038_nature06155
    DOI: 10.1038/nature06155
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    Cited by:

    1. In-Ja L. Byeon & Guillermo Calero & Ying Wu & Chang H. Byeon & Jinwon Jung & Maria DeLucia & Xiaohong Zhou & Simon Weiss & Jinwoo Ahn & Caili Hao & Jacek Skowronski & Angela M. Gronenborn, 2021. "Structure of HIV-1 Vpr in complex with the human nucleotide excision repair protein hHR23A," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    2. Charlotte Blessing & Katja Apelt & Diana Heuvel & Claudia Gonzalez-Leal & Magdalena B. Rother & Melanie Woude & Román González-Prieto & Adi Yifrach & Avital Parnas & Rashmi G. Shah & Tia Tyrsett Kuo &, 2022. "XPC–PARP complexes engage the chromatin remodeler ALC1 to catalyze global genome DNA damage repair," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    3. Corina Maritz & Reihaneh Khaleghi & Michelle N. Yancoskie & Sarah Diethelm & Sonja Brülisauer & Natalia Santos Ferreira & Yang Jiang & Shana J. Sturla & Hanspeter Naegeli, 2023. "ASH1L-MRG15 methyltransferase deposits H3K4me3 and FACT for damage verification in nucleotide excision repair," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    4. Benjamin Hilton & Sathyaraj Gopal & Lifang Xu & Sharmistha Mazumder & Phillip R Musich & Bongsup P Cho & Yue Zou, 2016. "Dissociation Dynamics of XPC-RAD23B from Damaged DNA Is a Determining Factor of NER Efficiency," PLOS ONE, Public Library of Science, vol. 11(6), pages 1-21, June.
    5. Jina Yu & Chunli Yan & Thomas Dodd & Chi-Lin Tsai & John A. Tainer & Susan E. Tsutakawa & Ivaylo Ivanov, 2023. "Dynamic conformational switching underlies TFIIH function in transcription and DNA repair and impacts genetic diseases," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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