A conserved RAD6-MDM2 ubiquitin ligase machinery targets histone chaperone ASF1A in tumorigenesis

Abstract

// Chen Wang 1, 2, 3, * , Jian-Feng Chang 1, 2, * , Hongli Yan 4, * , Da-Liang Wang 5 , Yan Liu 5 , Yuanya Jing 2 , Meng Zhang 2 , Yu-Long Men 2 , Dongdong Lu 2 , Xiao-Mei Yang 2 , Su Chen 1, 2, 6 , Fang-Lin Sun 1, 2 1 Research Center for Translational Medicine at East Hospital, Tongji University, Shanghai, 200120/200092, China 2 School of Life Sciences and Technology, Tongji University, Shanghai, 200120/200092, China 3 UN School of Environmental Sciences and Technology, Tongji University, Shanghai, 200120/200092, China 4 Department of Laboratory Medicine, Changhai Hospital, The Second Military Medical University, Shanghai, 200433, China 5 Institute of Epigenetics and Cancer Research, School of Medicine, Tsinghua University, Beijing, 100084, China 6 Department of Science and Education, People’s Hospital of Zunhua, Tangshan, Hebei, 064200, China * These authors have contributed equally to this work Correspondence to: Fang-Lin Sun, e-mail: sfl@tongji.edu.cn Su Chen, e-mail: chensu@tongji.edu.cn Xiao-Mei Yang, e-mail: yxm411@tongji.edu.cn Keywords: RAD6, MDM2, ASF1A, protein degradation, tumorigenesis Received: March 06, 2015      Accepted: August 12, 2015      Published: August 22, 2015 ABSTRACT Chromatin is a highly organized and dynamic structure in eukaryotic cells. The change of chromatin structure is essential in many cellular processes, such as gene transcription, DNA damage repair and others. Anti-silencing function 1 (ASF1) is a histone chaperone that participates in chromatin higher-order organization and is required for appropriate chromatin assembly. In this study, we identified the E2 ubiquitin-conjugating enzyme RAD6 as an evolutionary conserved interacting protein of ASF1 in D. melanogaster and H. sapiens that promotes the turnover of ASF1A by cooperating with a well-known E3 ligase, MDM2, via ubiquitin-proteasome pathway in H. sapiens . Further functional analyses indicated that the interplay between RAD6 and ASF1A associates with tumorigenesis. Together, these data suggest that the RAD6-MDM2 ubiquitin ligase machinery is critical for the degradation of chromatin-related proteins.