Tankyrase1-mediated poly(ADP-ribosyl)ation of TRF1 maintains cell survival after telomeric DNA damage

被引：25

作者：

Yang, Lu ^{[1
,2
,3
]}

Sun, Luxi ^{[1
,2
,3
]}

Teng, Yaqun ^{[1
,2
,3
]}

Chen, Hao ^{[1
,2
,3
]}

Gao, Ying ^{[1
,2
,3
]}

Levine, Arthur S. ^{[2
,3
]}

Nakajima, Satoshi ^{[2
,3
]}

Lan, Li ^{[2
,3
]}

机构：

[1] Tsinghua Univ, Sch Med, 1 Tsinghua Yuan, Beijing 100084, Peoples R China

[2] Univ Pittsburgh, Canc Inst, Sch Med, 5117 Ctr Ave, Pittsburgh, PA 15213 USA

[3] Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, 450 Technology Dr,523 Bridgeside Point 2, Pittsburgh, PA 15219 USA

来源：

NUCLEIC ACIDS RESEARCH | 2017年 / 45卷 / 07期

基金：

美国国家卫生研究院;

关键词：

STRAND BREAK REPAIR; STRUCTURAL BASIS; PROTEINS TRF1; LIGASE-III; TANKYRASE; POLYMERASE; STABILITY; CANCER; DISEASE; DOMAIN;

D O I：

10.1093/nar/gkx083

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 beta 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.

引用

页码：3906 / 3921

页数：16

共 68 条

[21] How the human telomeric proteins TRF1 and TRF2 recognize telomeric DNA: a view from high-resolution crystal structures [J].