title: Rap1 is indispensable for TRF2 function in etoposide-induced DNA damage response in gastric cancer cell line.
abstract: The telomeric protein TRF2, involving in telomeric and extratelomeric DNA damage response, has been previously reported to facilitate multidrug resistance (MDR) in gastric cancer cells by interfering ATM-dependent DNA damage response induced by anticancer drugs. Rap1 is the TRF2-interacting protein in the shelterin complex. Complex formation between Rap1 and TRF2 is essential for their function in telomere and end protection. Here we focus on the effects of Rap1 on TRF2 function in DNA damage response induced by anticancer drugs. Both Rap1 and TRF2 expression were upregulated in SGC7901 and its MDR variant SGC7901/VCR after etoposide treatment, which was more marked in SGC7901/VCR than in SGC7901. Rap1 silencing by siRNA in SGC7901/VCR partially reversed the etoposide resistance. And Rap1 silencing partially reversed the TRF2-mediated resistance to etoposide in SGC7901. Rap1 silencing did not affect the TRF2 upregulation induced by etoposide, but eliminated the inhibition effect of TRF2 on ATM expression and ATM phosphorylation at serine 1981 (ATM pS1981). Furthermore, phosphorylation of ATM targets, including γH2AX and serine 15 (S15) on p53, were increased in Rap1 silencing cells in response to etoposide. Thus, we confirm that Rap1, interacting with TRF2 in the shelterin complex, also has an important role in TRF2-mediated DNA damage response in gastric cancer cells treated by etoposide.
authors.affiliation: Department of Neurology, Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.affiliation: Department V of Digestive Diseases, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department V of Digestive Diseases, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department V of Digestive Diseases, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: L
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department V of Digestive Diseases, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department V of Digestive Diseases, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: H
authors.initials: H
authors.lastname: Wen
authors.affiliation: Department V of Digestive Diseases, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: H
authors.initials: H
authors.lastname: Ning
authors.affiliation: Department V of Digestive Diseases, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department II of Digestive Diseases, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China.
authors.forename: D
authors.initials: D
authors.lastname: Fan
references.citation: Cell Cycle. 2010 Oct 15;9(20):4061-7
references.pmid: 20948311
references.citation: Nat Genet. 2005 Feb;37(2):193-7
references.pmid: 15665826
references.citation: Free Radic Biol Med. 2012 Sep 1;53(5):1192-7
references.pmid: 22841872
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15539-44
references.pmid: 16223874
references.citation: Genes Dev. 2005 Sep 15;19(18):2100-10
references.pmid: 16166375
references.citation: Cancer Biol Ther. 2006 Aug;5(8):950-6
references.pmid: 16760674
references.citation: Nat Genet. 2005 Feb;37(2):116-8
references.pmid: 15678140
references.citation: Mol Cell Biol. 2009 Jul;29(13):3597-604
references.pmid: 19398584
references.citation: Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13068-73
references.pmid: 17670947
references.citation: PLoS Biol. 2004 Aug;2(8):E240
references.pmid: 15314656
references.citation: J Biol Chem. 2012 Dec 7;287(50):41583-94
references.pmid: 23086976
references.citation: J Biol Chem. 2010 Jan 8;285(2):1457-67
references.pmid: 19864690
references.citation: Tumour Biol. 2013 Apr;34(2):723-33
references.pmid: 23247865
references.citation: Cell Res. 2011 Jul;21(7):1013-27
references.pmid: 21423278
references.citation: Int J Biochem Cell Biol. 2012 Sep;44(9):1531-40
references.pmid: 22728163
references.citation: Science. 2010 Mar 26;327(5973):1657-61
references.pmid: 20339076