SLX4 Assembles a Telomere Maintenance Toolkit by Bridging Multiple Endonucleases with Telomeres
Bingbing Wan,
Jinhu Yin,
Kent Horvath,
Jaya Sarkar,
Yong Chen,
Jian Wu,
Ke Wan,
Jian Lu,
Peili Gu,
Eun Young Yu,
Neal F. Lue,
Sandy Chang,
Yie Liu,
Ming Lei
Affiliations
Bingbing Wan
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
Jinhu Yin
Laboratory of Molecular Gerontology, National Institute on Aging/National Institute of Health, 251 Bayview Drive, Baltimore, MD 21044, USA
Kent Horvath
Laboratory of Molecular Gerontology, National Institute on Aging/National Institute of Health, 251 Bayview Drive, Baltimore, MD 21044, USA
Jaya Sarkar
Laboratory of Molecular Gerontology, National Institute on Aging/National Institute of Health, 251 Bayview Drive, Baltimore, MD 21044, USA
Yong Chen
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
Jian Wu
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
Ke Wan
Howard Hughes Medical Institute, University of Michigan Medical School, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, USA
Jian Lu
Laboratory of Molecular Gerontology, National Institute on Aging/National Institute of Health, 251 Bayview Drive, Baltimore, MD 21044, USA
Peili Gu
Department of Laboratory Medicine and Pathology, Yale University School of Medicine, 330 Cedar Street, New Haven, CT 06520, USA
Eun Young Yu
Department of Microbiology and Immunology, W. R. Hearst Microbiology Research Center, Weill Medical College of Cornell University, New York, NY 10065, USA
Neal F. Lue
Department of Microbiology and Immunology, W. R. Hearst Microbiology Research Center, Weill Medical College of Cornell University, New York, NY 10065, USA
Sandy Chang
Department of Laboratory Medicine and Pathology, Yale University School of Medicine, 330 Cedar Street, New Haven, CT 06520, USA
Yie Liu
Laboratory of Molecular Gerontology, National Institute on Aging/National Institute of Health, 251 Bayview Drive, Baltimore, MD 21044, USA
Ming Lei
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
SLX4 interacts with several endonucleases to resolve structural barriers in DNA metabolism. SLX4 also interacts with telomeric protein TRF2 in human cells. The molecular mechanism of these interactions at telomeres remains unknown. Here, we report the crystal structure of the TRF2-binding motif of SLX4 (SLX4TBM) in complex with the TRFH domain of TRF2 (TRF2TRFH) and map the interactions of SLX4 with endonucleases SLX1, XPF, and MUS81. TRF2 recognizes a unique HxLxP motif on SLX4 via the peptide-binding site in its TRFH domain. Telomeric localization of SLX4 and associated nucleases depend on the SLX4-endonuclease and SLX4-TRF2 interactions and the protein levels of SLX4 and TRF2. SLX4 assembles an endonuclease toolkit that negatively regulates telomere length via SLX1-catalyzed nucleolytic resolution of telomere DNA structures. We propose that the SLX4-TRF2 complex serves as a double-layer scaffold bridging multiple endonucleases with telomeres for recombination-based telomere maintenance.
