5U6Z

Crystal Structure of Xenopus laevis Apex2 C-terminal Znf-GRF Domain

Summary for 5U6Z

• Entry DOI: 10.2210/pdb5u6z/pdb
• Descriptor: DNA-(apurinic or apyrimidinic site) lyase, ZINC ION, SULFATE ION, ... (4 entities in total)
• Functional Keywords: grf zinc finger, 3' ap endo/exonuclease, dna binding, lyase
• Biological source: Xenopus laevis (African clawed frog)
• Cellular location: Nucleus : Q6DDT4
• Total number of polymer chains: 1
• Total formula weight: 8433.98

Authors

Wallace, B.D.,Williams, R.S. (deposition date: 2016-12-09, release date: 2017-01-11, Last modification date: 2024-03-06)

Primary citation

Wallace, B.D.,Berman, Z.,Mueller, G.A.,Lin, Y.,Chang, T.,Andres, S.N.,Wojtaszek, J.L.,DeRose, E.F.,Appel, C.D.,London, R.E.,Yan, S.,Williams, R.S.
APE2 Zf-GRF facilitates 3'-5' resection of DNA damage following oxidative stress.
Proc. Natl. Acad. Sci. U.S.A., 114:304-309, 2017

PubMed Abstract: The Xenopus laevis APE2 (apurinic/apyrimidinic endonuclease 2) nuclease participates in 3'-5' nucleolytic resection of oxidative DNA damage and activation of the ATR-Chk1 DNA damage response (DDR) pathway via ill-defined mechanisms. Here we report that APE2 resection activity is regulated by DNA interactions in its Zf-GRF domain, a region sharing high homology with DDR proteins Topoisomerase 3α (TOP3α) and NEIL3 (Nei-like DNA glycosylase 3), as well as transcription and RNA regulatory proteins, such as TTF2 (transcription termination factor 2), TFIIS, and RPB9. Biochemical and NMR results establish the nucleic acid-binding activity of the Zf-GRF domain. Moreover, an APE2 Zf-GRF X-ray structure and small-angle X-ray scattering analyses show that the Zf-GRF fold is typified by a crescent-shaped ssDNA binding claw that is flexibly appended to an APE2 endonuclease/exonuclease/phosphatase (EEP) catalytic core. Structure-guided Zf-GRF mutations impact APE2 DNA binding and 3'-5' exonuclease processing, and also prevent efficient APE2-dependent RPA recruitment to damaged chromatin and activation of the ATR-Chk1 DDR pathway in response to oxidative stress in Xenopus egg extracts. Collectively, our data unveil the APE2 Zf-GRF domain as a nucleic acid interaction module in the regulation of a key single-strand break resection function of APE2, and also reveal topologic similarity of the Zf-GRF to the zinc ribbon domains of TFIIS and RPB9.

PubMed: 28028224
DOI: 10.1073/pnas.1610011114

Experimental method

X-RAY DIFFRACTION (2.6 Å)