Rap1 regulates hematopoietic stem cell survival and affects oncogenesis and response to chemotherapy

被引:47
作者
Khattar, Ekta [1 ]
Maung, Kyaw Ze Ya [1 ]
Chew, Chen Li [1 ]
Ghosh, Arkasubhra [1 ]
Mok, Michelle Meng Huang [2 ]
Lee, Pei [3 ]
Zhang, Jun [4 ]
Chor, Wei Hong Jeff [1 ]
Cildir, Gokhan [1 ,3 ]
Wang, Chelsia Qiuxia [1 ]
Mohd-Ismail, Nur Khairiah [1 ]
Chin, Desmond Wai Loon [2 ]
Lee, Soo Chin [2 ]
Yang, Henry [2 ]
Shin, Yong-Jae [5 ]
Nam, Do-Hyun [5 ]
Chen, Liming [4 ]
Kumar, Alan Prem [2 ]
Deng, Lih Wen [3 ]
Ikawa, Masahito [6 ,7 ]
Gunaratne, Jayantha [1 ]
Osato, Motomi [2 ]
Tergaonkar, Vinay [1 ,8 ]
机构
[1] ASTAR, IMCB, Singapore, Singapore
[2] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore, Singapore
[3] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore, Singapore
[4] Nanjing Normal Univ, Coll Life Sci, Jiangsu Key Lab Mol & Med Biotechnol, Nanjing 210023, Jiangsu, Peoples R China
[5] Samsung Med Ctr, Inst Refractory Canc Res, Seoul, South Korea
[6] Osaka Univ, Res Inst Microbial Dis, Suita, Osaka 5650871, Japan
[7] Osaka Univ, Grad Sch Med, Suita, Osaka 5650871, Japan
[8] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pathol, Singapore, Singapore
基金
英国医学研究理事会;
关键词
MUTANT TERT PROMOTER; DOUBLE-STRAND BREAKS; NF-KAPPA-B; DNA-DAMAGE; GENE-EXPRESSION; C-MYC; TELOMERIC DNA; COMPLEX; ATM; REPAIR;
D O I
10.1038/s41467-019-13082-9
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Increased levels and non-telomeric roles have been reported for shelterin proteins, including RAP1 in cancers. Herein using Rap1 null mice, we provide the genetic evidence that mammalian Rap1 plays a major role in hematopoietic stem cell survival, oncogenesis and response to chemotherapy. Strikingly, this function of RAP1 is independent of its association with the telomere or with its known partner TRF2. We show that RAP1 interacts with many members of the DNA damage response (DDR) pathway. RAP1 depleted cells show reduced interaction between XRCC4/DNA Ligase IV and DNA-PK, and are impaired in DNA Ligase IV recruitment to damaged chromatin for efficient repair. Consistent with its role in DNA damage repair, RAP1 loss decreases double-strand break repair via NHEJ in vivo, and consequently reduces B cell class switch recombination. Finally, we discover that RAP1 levels are predictive of the success of chemotherapy in breast and colon cancer.
引用
收藏
页数:14
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