A conserved RAD6-MDM2 ubiquitin ligase machinery targets histone chaperone ASF1A in tumorigenesis.
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.
Research Center for Translational Medicine at East Hospital, Tongji University, Shanghai, 200120/200092, China.|School of Life Sciences and Technology, Tongji University, Shanghai, 200120/200092, China.|UN School of Environmental Sciences and Technology, Tongji University, Shanghai, 200120/200092, China.
Chen
C
Wang
Research Center for Translational Medicine at East Hospital, Tongji University, Shanghai, 200120/200092, China.|School of Life Sciences and Technology, Tongji University, Shanghai, 200120/200092, China.
Jian-Feng
JF
Chang
Department of Laboratory Medicine, Changhai Hospital, The Second Military Medical University, Shanghai, 200433, China.
Hongli
H
Yan
Institute of Epigenetics and Cancer Research, School of Medicine, Tsinghua University, Beijing, 100084, China.
Da-Liang
DL
Wang
Institute of Epigenetics and Cancer Research, School of Medicine, Tsinghua University, Beijing, 100084, China.
Yan
Y
Liu
School of Life Sciences and Technology, Tongji University, Shanghai, 200120/200092, China.
Yuanya
Y
Jing
School of Life Sciences and Technology, Tongji University, Shanghai, 200120/200092, China.
Meng
M
Zhang
School of Life Sciences and Technology, Tongji University, Shanghai, 200120/200092, China.
Yu-Long
YL
Men
School of Life Sciences and Technology, Tongji University, Shanghai, 200120/200092, China.
Dongdong
D
Lu
School of Life Sciences and Technology, Tongji University, Shanghai, 200120/200092, China.
Xiao-Mei
XM
Yang
Research Center for Translational Medicine at East Hospital, Tongji University, Shanghai, 200120/200092, China.|School of Life Sciences and Technology, Tongji University, Shanghai, 200120/200092, China.|Department of Science and Education, People's Hospital of Zunhua, Tangshan, Hebei, 064200, China.
Su
S
Chen
Research Center for Translational Medicine at East Hospital, Tongji University, Shanghai, 200120/200092, China.|School of Life Sciences and Technology, Tongji University, Shanghai, 200120/200092, China.
Fang-Lin
FL
Sun
D000818:Animals; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018613:Microscopy, Confocal; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
C491641:ASF1A protein, human; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D006657:Histones; D018832:Molecular Chaperones; C471545:UBE2A protein, human; C471546:UBE2B protein, human; D044763:Ubiquitin-Conjugating Enzymes; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
ASF1A; MDM2; RAD6; protein degradation; tumorigenesis