Abstract
The SLX1-SLX4 complex is a structure-specific endonuclease that cleaves branched DNA structures and plays significant roles in DNA recombination and repair in eukaryotic cells. The heterodimeric interaction between SLX1 and SLX4 is essential for the endonuclease activity of SLX1. Here, we present the crystal structure of Slx1 C-terminal zinc finger domain in complex with the C-terminal helix-turn-helix domain of Slx4 from Schizosaccharomyces pombe at 2.0 Å resolution. The structure reveals a conserved binding mechanism underling the Slx1-Slx4 interaction. Structural and sequence analyses indicate Slx1 C-terminal domain is actually an atypical C4HC3-type RING finger which normally possesses E3 ubiquitin ligase activity, but here is absolutely required for Slx1 interaction with Slx4. Furthermore, we found the C-terminal tail of S. pombe Slx1 contains a SUMO-interacting motif and can recognize Pmt3 (S. pombe SUMO), suggesting that Slx1-Slx4 complex could be recruited by SUMOylated protein targets to take part in replication associated DNA repair processes.
Highlights
Multi-domain containing scaffold protein SLX4 has been shown to interact with a group of proteins including SLX1, MUS81-EME1 and XPF-ERCC1 and coordinates these endonucleases for the resolution of Holiday junctions or interstrand crosslinks structures[1,2,3,4,5,6,7,8]
SLX4 has been reported to bind to telomeric protein TRF2 to preserve telomere[9]
A number of observations have suggested that yeast Slx1-Slx[4] complex plays a role in maintaining the integrity of the ribosomal DNA loci during S phase[17,18,19]
Summary
Multi-domain containing scaffold protein SLX4 ( known as BTBD12) has been shown to interact with a group of proteins including SLX1 ( known as GIYD2), MUS81-EME1 and XPF-ERCC1 and coordinates these endonucleases for the resolution of Holiday junctions or interstrand crosslinks structures[1,2,3,4,5,6,7,8]. SLX4 contains tandem UBZ4 domains and multiple SUMO-interacting motifs (SIMs) that have been demonstrated to be critical for SLX4 to bind to specific ubiquitinated or SUMOylated genome integrity maintenance proteins to process different types of DNA lesions[11,12,13,14]. Considerable progress has been made in understanding how SLX4-coordinated protein complex functions to preserve genome integrity, the precise mechanism by which SLX4 complex resolves the Holliday junctions at the molecular level has yet to emerge. Slx[1] C-terminal zinc finger and Slx[4] C-terminal helix-turn-helix domain are well conserved throughout evolution (Supplementary Figs S1A and B), and have been mapped out to be the minimal fragment of each protein required for the complex formation[1,2]. We uncover the C-terminal tail SUMO-interacting motif of S. pombe Slx[1] binds SUMO, which imply that S. pombe Slx1-Slx[4] complex can be recruited by SUMOylated proteins to involve in the DNA damage response
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