期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 295, 期 46, 页码 15566-15575出版社
ELSEVIER
DOI: 10.1074/jbc.RA120.015541
关键词
base excision repair (BER); DNA glycosylase; interstrand DNA cross-link; GRF; zinc finger; DNA repair; DNA-binding protein; DNA damage; crystallography; nucleic acid enzymology; DNA– protein interaction; X-ray crystallography
资金
- National Institutes of Health [R01GM131071, P01CA092584]
- NIEHS, National Institute of Health Intramural Program [1Z01ES102765]
- Vanderbilt Molecular Biophysics Training Program [T32GM08320]
- National Science Foundation Graduate Research Fellowship [DGE-1445197]
The NEIL3 DNA glycosylase maintains genome integrity during replication by excising oxidized bases from single-stranded DNA (ssDNA) and unhooking interstrand cross-links (ICLs) at fork structures. In addition to its N-terminal catalytic glycosylase domain, NEIL3 contains two tandem C-terminal GRF-type zinc fingers that are absent in the other NEIL paralogs. ssDNA binding by the GRF-ZF motifs helps recruit NEIL3 to replication forks converged at an ICL, but the nature of DNA binding and the effect of the GRF-ZF domain on catalysis of base excision and ICL unhooking is unknown. Here, we show that the tandem GRF-ZFs of NEIL3 provide affinity and specificity for DNA that is greater than each individual motif alone. The crystal structure of the GRF domain shows that the tandem ZF motifs adopt a flexible head-to-tail configuration well-suited for binding to multiple ssDNA conformations. Functionally, we establish that the NEIL3 GRF domain inhibits glycosylase activity against monoadducts and ICLs. This autoinhibitory activity contrasts GRF-ZF domains of other DNA-processing enzymes, which typically use ssDNA binding to enhance catalytic activity, and suggests that the C-terminal region of NEIL3 is involved in both DNA damage recruitment and enzymatic regulation.
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