A winged helix domain in human MUS81 binds DNA and modulates the endonuclease activity of MUS81 complexes

The MUS81-EME1 endonuclease maintains metazoan genomic integrity by cleaving branched DNA structures that arise during the resolution of recombination intermediates. In humans, MUS81 also forms a poorly characterized complex with EME2. Here, we identify and determine the structure of a winged helix (WH) domain from human MUS81, which binds DNA. WH domain mutations greatly reduce binding of the isolated domain to DNA and impact on incision activity of MUS81-EME1/EME2 complexes. Deletion of the WH domain reduces the endonuclease activity of both MUS81-EME1 and MUS81-EME2 complexes, and incisions made by MUS81-EME2 are made closer to the junction on substrates containing a downstream duplex, such as fork structures and nicked Holliday junctions. WH domain mutation or deletion in Schizosaccharomyces pombe phenocopies the DNA-damage sensitivity of strains deleted for mus81. Our results indicate an important role for the WH domain in both yeast and human MUS81 complexes.

• Publication year

  2013

• Venue

  Nucleic Acids Research

• Publication date

  2013-08-27

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1093/nar/gkt760PMID 23982516PMCID 3834828
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Human MUS81 complexes stimulate flap endonuclease 1

  2012cited by this paper
• Genetic and functional interactions between Mus81–Mms4 and Rad27

  2010cited by this paper
• Mammalian BTBD12/SLX4 assembles a Holliday junction resolvase and is required for DNA repair.

  2009cited by this paper
• Human SLX4 is a Holliday junction resolvase subunit that binds multiple DNA repair/recombination endonucleases.

  2009cited by this paper
• Coordination of structure-specific nucleases by human SLX4/BTBD12 is required for DNA repair.

  2009cited by this paper
• A junction branch point adjacent to a DNA backbone nick directs substrate cleavage by Saccharomyces cerevisiae Mus81-Mms4

  2009cited by this paper
• Protein structure prediction on the Web: a case study using the Phyre server

  2009cited by this paper
• Gene tagging and gene replacement using recombinase-mediated cassette exchange in Schizosaccharomyces pombe.

  2008cited by this paper
• Crystal structure of the Mus81-Eme1 complex.

  2008influential reference
• Identification of Holliday junction resolvases from humans and yeast

  2008cited by this paper
• Cleavage mechanism of human Mus81–Eme1 acting on Holliday-junction structures

  2008cited by this paper
• Structural and functional relationships of the XPF/MUS81 family of proteins.

  2008cited by this paper
• Identification of FAAP24, a Fanconi anemia core complex protein that interacts with FANCM.

  2007cited by this paper
• Exploring the roles of Mus81-Eme1/Mms4 at perturbed replication forks.

  2007cited by this paper
• Structural and functional analyses of an archaeal XPF/Rad1/Mus81 nuclease: asymmetric DNA binding and cleavage mechanisms.

  2005cited by this paper
• Structure of an XPF endonuclease with and without DNA suggests a model for substrate recognition

  2005cited by this paper
• BLM helicase facilitates Mus81 endonuclease activity in human cells.

  2005influential reference
• The structure of the human ERCC1/XPF interaction domains reveals a complementary role for the two proteins in nucleotide excision repair.

  2005cited by this paper
• Structural Determinants of Metal Selectivity in Prokaryotic Metal-responsive Transcriptional Regulators

  2005cited by this paper
• Identification and Characterization of the Human Mus81-Eme1 Endonuclease*

  2003influential reference
• RNA interference inhibition of Mus81 reduces mitotic recombination in human cells.

  2003cited by this paper
• Functional domains required for the Saccharomyces cerevisiae Mus81-Mms4 endonuclease complex formation and nuclear localization.

  2003cited by this paper
• Holliday junction resolution in human cells: two junction endonucleases with distinct substrate specificities

  2002cited by this paper
• The active site of the DNA repair endonuclease XPF–ERCC1 forms a highly conserved nuclease motif

  2002cited by this paper
• Human Mus81-associated endonuclease cleaves Holliday junctions in vitro.

  2001cited by this paper
• Mus81-Eme1 are essential components of a Holliday junction resolvase.

  2001cited by this paper
• A novel interactive tool for rigid-body modeling of multi-domain macromolecules using residual dipolar couplings

  2001cited by this paper
• Winged helix proteins.

  2000cited by this paper
• Alignment of Biological Macromolecules in Novel Nonionic Liquid Crystalline Media for NMR Experiments

  2000cited by this paper
• Protein backbone angle restraints from searching a database for chemical shift and sequence homology

  1999cited by this paper
• Influence of non-bonded parameters on the quality of NMR structures: A new force field for NMR structure calculation

  1999cited by this paper
• Crystal structure of a cobalt-activated diphtheria toxin repressor-DNA complex reveals a metal-binding SH3-like domain.

  1999cited by this paper
• Crystallography & NMR system: A new software suite for macromolecular structure determination.

  1998cited by this paper
• Measurement of J and dipolar couplings from simplified two-dimensional NMR spectra.

  1998cited by this paper
• Structure of the metal-ion-activated diphtheria toxin repressor/ tox operator complex

  1998cited by this paper
• Persistent initiation of DNA replication and chromatin-bound MCM proteins during the cell cycle in cdc6 mutants.

  1997cited by this paper
• NMRPipe: A multidimensional spectral processing system based on UNIX pipes

  1995cited by this paper
• 1H, 13C and 15N random coil NMR chemical shifts of the common amino acids. I. Investigations of nearest-neighbor effects

  1995cited by this paper

• Potential wMUS81 inhibitory activity of triterpenoids isolated from Helicteres hirsuta and Pterospermum truncatolobatum: A molecular docking studies

  2023cites this paper
• MUS81 is required for atypical recombination intermediate resolution but not crossover designation in rice.

  2022cites this paper
• Crystal structure of the human MUS81-EME2 complex.

  2022cites this paper
• Marine derivatives prevent wMUS81 in silico studies

  2021cites this paper
• Changes in DNA damage repair gene expression and cell cycle gene expression do not explain radioresistance in tamoxifen-resistant breast cancer.

  2020cites this paper
• Computational investigation of possible inhibitors of the winged-helix domain of MUS81.

  2020cites this paper
• Mechanisms of cross-resistance to radiotherapy and tamoxifen treatment in breast cancer

  2019cites this paper
• Structure of the Pol II initation complex with TFIIH and core Mediator and mechanistic implications for transcription

  2018cites this paper
• Control of structure-specific endonucleases to maintain genome stability

  2017cites this paper
• Structures of transcription pre-initiation complex with TFIIH and Mediator

  2017cites this paper
• Optimizing the large-scale production of Saw1 and the Saw1-Rad1-Rad10 nuclease complex for structural studies

  2017cites this paper
• Upregulated LINE-1 Activity in the Fanconi Anemia Cancer Susceptibility Syndrome Leads to Spontaneous Pro-inflammatory Cytokine Production

  2016cites this paper
• Structure and mechanism of nucleases regulated by SLX4.

  2016cites this paper
• A physiological significance of the functional interaction between Mus81 and Rad27 in homologous recombination repair

  2015cites this paper
• DNA damage repair machinery and HIV escape from innate immune sensing

  2014cites this paper
• Human MUS81-EME2 can cleave a variety of DNA structures including intact Holliday junction and nicked duplex

  2014influential citation