Human Holliday junction resolvase GEN1 uses a chromodomain for efficient DNA recognition and cleavage

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Abstract

Holliday junctions (HJs) are key DNA intermediates in homologous recombination. They link homologous DNA strands and have to be faithfully removed for proper DNA segregation and genome integrity. Here, we present the crystal structure of human HJ resolvase GEN1 complexed with DNA at 3.0 Å resolution. The GEN1 core is similar to other Rad2/XPG nucleases. However, unlike other members of the superfamily, GEN1 contains a chromodomain as an additional DNA interaction site. Chromodomains are known for their chromatin-targeting function in chromatin remodelers and histone(de)acetylases but they have not previously been found in nucleases. The GEN1 chromodomain directly contacts DNA and its truncation severely hampers GEN1's catalytic activity. Structure-guided mutations in vitroand in vivo in yeast validated our mechanistic findings. Our study provides the missing structure in the Rad2/XPG family and insights how a well-conserved nuclease core acquires versatility in recognizing diverse substrates for DNA repair and maintenance.

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Shun-Hsiao Lee

Department of Structural Cell Biology, Molecular Mechanisms of DNA Repair, Max Planck Institute of Biochemistry, Martinsried, Germany

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The authors declare that no competing interests exist.
Lissa Nicola Princz

Department of Molecular Cell Biology, DNA Replication and Genome Integrity, Max Planck Institute of Biochemistry, Martinsried, Germany

Competing interests
The authors declare that no competing interests exist.
Maren Felizitas Klügel

Department of Structural Cell Biology, Molecular Mechanisms of DNA Repair, Max Planck Institute of Biochemistry, Martinsried, Germany

Competing interests
The authors declare that no competing interests exist.
Bianca Habermann

Computational Biology, Max Planck Institute of Biochemistry, Martinsried, Germany

Competing interests
The authors declare that no competing interests exist.
Boris Pfander

Department of Molecular Cell Biology, DNA Replication and Genome Integrity, Max Planck Institute of Biochemistry, Martinsried, Germany

Competing interests
The authors declare that no competing interests exist.
Christian Biertümpfel

Department of Structural Cell Biology, Molecular Mechanisms of DNA Repair, Max Planck Institute of Biochemistry, Martinsried, Germany

For correspondence
biertuempfel@biochem.mpg.de

Competing interests
The authors declare that no competing interests exist.

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