WRN is recruited to damaged telomeres via its RQC domain and tankyrase1-mediated poly-ADP-ribosylation of TRF1.
Werner syndrome (WS) is a progeroid-like syndrome caused by WRN gene mutations. WS cells exhibit shorter telomere length compared to normal cells, but it is not fully understood how WRN deficiency leads directly to telomere dysfunction. By generating localized telomere-specific DNA damage in a real-time fashion and a dose-dependent manner, we found that the damage response of WRN at telomeres relies on its RQC domain, which is different from the canonical damage response at genomic sites via its HRDC domain. We showed that in addition to steady state telomere erosion, WRN depleted cells are also sensitive to telomeric damage. WRN responds to site-specific telomeric damage via its RQC domain, interacting at Lysine 1016 and Phenylalanine1037 with the N-terminal acidic domain of the telomere shelterin protein TRF1 and demonstrating a novel mechanism for WRN's role in telomere protection. We also found that tankyrase1-mediated poly-ADP-ribosylation of TRF1 is important for both the interaction between WRN and TRF1 and the damage recruitment of WRN to telomeres. Mutations of potential tankyrase1 ADP-ribosylation sites within the RGCADG motif of TRF1 strongly diminish the interaction with WRN and the damage response of WRN only at telomeres. Taken together, our results reveal a novel mechanism as to how WRN protects telomere integrity from damage and telomere erosion.
School of Medicine, Tsinghua University, No.1 Tsinghua Yuan, Haidian District, Beijing 100084, China.|University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.|Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 450 Technology Drive, 523 Bridgeside Point II, Pittsburgh, PA 15219, USA.
Luxi
L
Sun
University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.|Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 450 Technology Drive, 523 Bridgeside Point II, Pittsburgh, PA 15219, USA.
Satoshi
S
Nakajima
School of Medicine, Tsinghua University, No.1 Tsinghua Yuan, Haidian District, Beijing 100084, China.|University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.|Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 450 Technology Drive, 523 Bridgeside Point II, Pittsburgh, PA 15219, USA.
Yaqun
Y
Teng
School of Medicine, Tsinghua University, No.1 Tsinghua Yuan, Haidian District, Beijing 100084, China.|University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.|Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 450 Technology Drive, 523 Bridgeside Point II, Pittsburgh, PA 15219, USA.
Hao
H
Chen
School of Medicine, Tsinghua University, No.1 Tsinghua Yuan, Haidian District, Beijing 100084, China.|University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.|Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 450 Technology Drive, 523 Bridgeside Point II, Pittsburgh, PA 15219, USA.
Lu
L
Yang
University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.|Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 450 Technology Drive, 523 Bridgeside Point II, Pittsburgh, PA 15219, USA.
Xiukai
X
Chen
University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.
Boya
B
Gao
University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.|Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 450 Technology Drive, 523 Bridgeside Point II, Pittsburgh, PA 15219, USA.
Arthur S
AS
Levine
University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.|Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 450 Technology Drive, 523 Bridgeside Point II, Pittsburgh, PA 15219, USA.
Li
L
Lan
D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D010084:Oxidation-Reduction; D054730:Protein Interaction Domains and Motifs; D017382:Reactive Oxygen Species / Q000378:metabolism; D038501:Tankyrases / Q000378:metabolism*; D016615:Telomere / Q000201:enzymology* / Q000378:metabolism; D035321:Telomeric Repeat Binding Protein 1 / Q000737:chemistry / Q000378:metabolism*; D000071657:Werner Syndrome Helicase / Q000737:chemistry / Q000378:metabolism*
D017382:Reactive Oxygen Species; D038501:Tankyrases; D035321:Telomeric Repeat Binding Protein 1; D000071657:Werner Syndrome Helicase; C418109:TNKS protein, human; C098785:WRN protein, human