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

Ekta Khattar, Kyaw Ze Ya Maung, Chen Li Chew, Arkasubhra Ghosh, Michelle Meng Huang Mok, Pei Lee, Jun Zhang, Wei Hong Jeff Chor, Gökhan Cildir, Chelsia Qiuxia Wang, Nur Khairiah Mohd-Ismail, Desmond Wai Loon Chin, Soo Chin Lee, Henry Yang, Yong-Jae Shin, Do-Hyun Nam, Liming Chen, Alan Prem Kumar, Lih Wen Deng, Masahito Ikawa, Jayantha Gunaratne, Motomi Osato and Vinay Tergaonkar ()
Additional contact information
Ekta Khattar: Agency for Science, Technology and Research (A-STAR)
Kyaw Ze Ya Maung: Agency for Science, Technology and Research (A-STAR)
Chen Li Chew: Agency for Science, Technology and Research (A-STAR)
Arkasubhra Ghosh: Agency for Science, Technology and Research (A-STAR)
Michelle Meng Huang Mok: National University of Singapore
Pei Lee: National University of Singapore
Jun Zhang: Nanjing Normal University
Wei Hong Jeff Chor: Agency for Science, Technology and Research (A-STAR)
Gökhan Cildir: Agency for Science, Technology and Research (A-STAR)
Chelsia Qiuxia Wang: Agency for Science, Technology and Research (A-STAR)
Nur Khairiah Mohd-Ismail: Agency for Science, Technology and Research (A-STAR)
Desmond Wai Loon Chin: National University of Singapore
Soo Chin Lee: National University of Singapore
Henry Yang: National University of Singapore
Yong-Jae Shin: Samsung Medical Center
Do-Hyun Nam: Samsung Medical Center
Liming Chen: Nanjing Normal University
Alan Prem Kumar: National University of Singapore
Lih Wen Deng: National University of Singapore
Masahito Ikawa: Osaka University
Jayantha Gunaratne: Agency for Science, Technology and Research (A-STAR)
Motomi Osato: National University of Singapore
Vinay Tergaonkar: Agency for Science, Technology and Research (A-STAR)

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-13082-9

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