Global re-wiring of p53 transcription regulation by the hepatitis B virus X protein.
The tumour suppressor p53 is a central player in transcription regulation and cell fate determination. By interacting with p53 and altering its sequence-specific binding to the response elements, the hepatitis B virus X protein (HBx) was reported to re-direct p53 regulation of some genes.



Coupling massively parallel deep sequencing with p53 chromatin immunoprecipitation, we demonstrate that HBx modulates global p53 site selection and that this was strongly influenced by altered interaction with transcription co-factors/co-regulators as well as post-translational modifications. Specifically, HBx attenuated p53-TBP-RB1 transcription complex recruitment and interaction and this was associated with hyper-phosphorylation of p53 at serine 315 by HBx. Concurrently, HBx enhanced p53 DNA occupancy to other response elements either alone by displacing specific transcription factors such as CEBPB and NFkB1, or in complex with distinct interacting co-factors Sp1, JUN and E2F1. Importantly, re-wiring of p53 transcription regulation by HBx was linked to the deregulation of genes involved in cell proliferation and death, suggesting a role of HBx in errant cell fate determination mediated by altered p53 site selection of target genes.



Our study thus presents first evidence of global modes of p53 transcription alteration by HBx and provides new insights to understand and potentially curtail the viral oncoprotein.
Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore 169610, Singapore; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore 117456, Singapore.
Cheryl
C
Chan
NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore 117456, Singapore; Duke-NUS Graduate Medical School, Singapore 169857, Singapore.
Thomas
T
Thurnherr
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
Jingbo
J
Wang
School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
Xavier
X
Gallart-Palau
School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
Siu Kwan
SK
Sze
Duke-NUS Graduate Medical School, Singapore 169857, Singapore.
Steve
S
Rozen
Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore 169610, Singapore; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore 117456, Singapore; Duke-NUS Graduate Medical School, Singapore 169857, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore. Electronic address: caroline_lee@nuhs.edu.sg.
Caroline G
CG
Lee
D016923:Cell Death; D049109:Cell Proliferation / Q000235:genetics; D017124:Conserved Sequence / Q000235:genetics; D004247:DNA / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008954:Models, Biological; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D020218:Response Elements / Q000235:genetics; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins
D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D010768:Phosphoserine; D004247:DNA
ChIP-Seq; HBx; P53 transcription; Phosphorylation; p53 serine 315