Tankyrase1-mediated poly(ADP-ribosyl)ation of TRF1 maintains cell survival after telomeric DNA damage.
Oxidative DNA damage triggers telomere erosion and cellular senescence. However, how repair is initiated at telomeres is largely unknown. Here, we found unlike PARP1-mediated Poly-ADP-Ribosylation (PARylation) at genomic damage sites, PARylation at telomeres is mainly dependent on tankyrase1 (TNKS1). TNKS1 is recruited to damaged telomeres via its interaction with TRF1, which subsequently facilitates the PARylation of TRF1 after damage. TNKS inhibition abolishes the recruitment of the repair proteins XRCC1 and polymerase β at damaged telomeres, while the PARP1/2 inhibitor only has such an effect at non-telomeric damage sites. The ANK domain of TNKS1 is essential for the telomeric damage response and TRF1 interaction. Mutation of the tankyrase-binding motif (TBM) on TRF1 (13R/18G to AA) disrupts its interaction with TNKS1 concomitant recruitment of TNKS1 and repair proteins after damage. Either TNKS1 inhibition or TBM mutated TRF1 expression markedly sensitizes cells to telomere oxidative damage as well as XRCC1 inhibition. Together, our data reveal a novel role of TNKS1 in facilitating SSBR at damaged telomeres through PARylation of TRF1, thereby protecting genome stability and cell viability.
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
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
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.
Ying
Y
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.
Satoshi
S
Nakajima
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
D002460:Cell Line; D002470:Cell Survival; D004249:DNA Damage; D004260:DNA Repair; D042822:Genomic Instability; D006801:Humans; D038501:Tankyrases / Q000378:metabolism*; D016615:Telomere / Q000201:enzymology*; D035321:Telomeric Repeat Binding Protein 1 / Q000378:metabolism*
D038501:Tankyrases; D035321:Telomeric Repeat Binding Protein 1; C418109:TNKS protein, human