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

• Published in: Nature communications Vol. 10; no. 1; pp. 5349 - 14
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.12.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/100; 13/106; 13/31; 13/51; 14; 14/19; 38; 38/1; 38/77; 631/337; 631/532; 631/67; 631/80; 692/4028; Animals; Antineoplastic Agents - pharmacology; Carcinogenesis - drug effects; Carcinogenesis - metabolism; Carcinogenesis - pathology; Cell Line; Cell survival; Cell Survival - drug effects; Cell Survival - radiation effects; Chemotherapy; Deoxyribonucleic acid; DNA; DNA Damage; DNA Ligase ATP - metabolism; DNA repair; DNA Repair - drug effects; DNA Repair - radiation effects; DNA-Activated Protein Kinase - metabolism; Fluorouracil - pharmacology; Gamma Rays; Genomic Instability - drug effects; Genomic Instability - radiation effects; Genotoxicity; Hematopoietic stem cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - radiation effects; Humanities and Social Sciences; Humans; Mice, Knockout; multidisciplinary; Mutagens - toxicity; Protein Binding - drug effects; Protein Binding - radiation effects; Proteins; Proto-Oncogene Proteins c-myc - metabolism; rap1 GTP-Binding Proteins - metabolism; Rap1 protein; Repair; Science; Science (multidisciplinary); Sensitivity enhancement; Stem cells; Survival Analysis; Telomere-Binding Proteins - metabolism; Tumorigenesis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-13082-9

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. Rap1 is a telomeric protein that is highly expressed in cancers. Here, the authors show that Rap1 interacts with several DNA repair proteins independent of its telomere function to enhance DNA repair and that its deficiency leads to accelerated tumorigenesis, but enhanced sensitivity to genotoxic stress.