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

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...

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Detalles Bibliográficos
Autores principales: Khattar, Ekta, Maung, Kyaw Ze Ya, Chew, Chen Li, Ghosh, Arkasubhra, Mok, Michelle Meng Huang, Lee, Pei, Zhang, Jun, Chor, Wei Hong Jeff, Cildir, Gökhan, Wang, Chelsia Qiuxia, Mohd-Ismail, Nur Khairiah, Chin, Desmond Wai Loon, Lee, Soo Chin, Yang, Henry, Shin, Yong-Jae, Nam, Do-Hyun, Chen, Liming, Kumar, Alan Prem, Deng, Lih Wen, Ikawa, Masahito, Gunaratne, Jayantha, Osato, Motomi, Tergaonkar, Vinay
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911077/
https://www.ncbi.nlm.nih.gov/pubmed/31836706
http://dx.doi.org/10.1038/s41467-019-13082-9
Descripción
Sumario: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.