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ABSTRACT Impairment of the circadian clock is linked to cancer development. However, whether the circadian clock is modulated by oncogenic receptor tyrosine kinases remains unclear. Here we

demonstrated that receptor tyrosine kinase activation promotes CK2-mediated CLOCK S106 phosphorylation and subsequent disassembly of the CLOCK–BMAL1 dimer and suppression of the downstream

gene expression in hepatocellular carcinoma (HCC) cells. In addition, CLOCK S106 phosphorylation exposes its nuclear export signal to bind Exportin1 for nuclear exportation. Cytosolic CLOCK

acetylates PRPS1/2 K29 and blocks HSC70-mediated and lysosome-dependent PRPS1/2 degradation. Stabilized PRPS1/2 promote de novo nucleotide synthesis and HCC cell proliferation and liver

tumour growth. Furthermore, CLOCK S106 phosphorylation and PRPS1/2 K29 acetylation are positively correlated in human HCC specimens and with HCC poor prognosis. These findings delineate a

critical mechanism by which oncogenic signalling inhibits canonical CLOCK transcriptional activity and simultaneously confers CLOCK with instrumental moonlighting functions to promote

nucleotide synthesis and tumour growth. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through

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support SIMILAR CONTENT BEING VIEWED BY OTHERS DNA POLYMERASE BETA CONNECTS TUMORIGENICITY WITH THE CIRCADIAN CLOCK IN LIVER CANCER THROUGH THE EPIGENETIC DEMETHYLATION OF _PER1_ Article

Open access 20 January 2024 CHROMATIN-ASSOCIATED OGT PROMOTES THE MALIGNANT PROGRESSION OF HEPATOCELLULAR CARCINOMA BY ACTIVATING ZNF263 Article 23 June 2023 ANTI-ONCOGENE PTPN13

INACTIVATION BY HEPATITIS B VIRUS X PROTEIN COUNTERACTS IGF2BP1 TO PROMOTE HEPATOCELLULAR CARCINOMA PROGRESSION Article Open access 13 October 2020 DATA AVAILABILITY Mass spectrometry data

have been deposited in ProteomeXchange with the accession code PXD037738. UniProt protein database (EMBL-EBI) was used for protein identification. All other data supporting the findings of

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Central  Google Scholar  Download references ACKNOWLEDGEMENTS This study was supported by grants from the Ministry of Science and Technology of the People’s Republic of China

(2020YFA0803300, Z.L.; 2021YFA0805600, D.X.), the National Natural Science Foundation of China (92157113 and 82072630, D.X.; 82173114, Z.W.; 82072903 and 82272872, T.L.; 82002811, M. Yan;

82188102 and 82030074, Z.L.), the Zhejiang Natural Science Foundation Key Project (LD22H160002, D.X.; LD21H160003, Z.L.), Zhejiang Natural Science Foundation Discovery Project (LQ22H160023,

Z.W.), and the Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang (2019R01001, Z.L.). Z.L. is the Kuancheng Wang Distinguished Chair. The authors received no specific

funding for this work. We express our great gratitude to Dr. Hong Wang and his team from the Hangzhou Cosmos Wisdom Mass Spectrometry Center of Zhejiang University Medical School for their

technical support in sample analysis utilizing an integrated nanoLC–ESI–MS/MS and data processing platform. AUTHOR INFORMATION Author notes * These authors contributed equally: Tong Liu,

Zheng Wang, Leiguang Ye, Yuran Duan. AUTHORS AND AFFILIATIONS * Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine,

Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China Tong Liu, Zheng Wang, Yuran Duan, Haiyan He, Liwei Xiao, Qingang Wu, Ke Wu, Guimei Ji, Yuli Shen, Lei Wang, Lin

Li, Peixiang Zheng, Bofei Dong, Zhimin Lu & Daqian Xu * Cancer Center, Zhejiang University, Hangzhou, China Tong Liu, Zheng Wang, Haiyan He, Liwei Xiao, Qingang Wu, Zhimin Lu & 

Daqian Xu * Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China Tong Liu * NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of

Harbin Medical University, Harbin, China Tong Liu & Zhiren Zhang * Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China Leiguang Ye * Harbin, China

Leiguang Ye * The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, Qingdao, China Hongfei Jiang & Fei Shao * Department of Cancer Biology, Department of

Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Yan Xia * Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy,

Ocean University of China, Qingdao, China Mengke Yang & Rilei Yu * Department of Pathology, Harbin Medical University, Harbin, China Meisi Yan * Department of Clinical Laboratory, Cancer

Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China Xu Qian

Authors * Tong Liu View author publications You can also search for this author inPubMed Google Scholar * Zheng Wang View author publications You can also search for this author inPubMed 

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View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS D.X. and Z.L. conceived and designed the study and wrote the manuscript. T.L., Z.W., L.Y.,

Y.D., H.H., K.W., M. Yan, G.J., Y.S., L.W., L.L., P.Z., B.D., F.S. and Z.Z. performed the experiments; H.J., M. Yang and R.Y. were involved in MD simulation analyses. Y.X., L.X., Q.W. and

X.Q. reviewed and edited the manuscript. CORRESPONDING AUTHORS Correspondence to Zhimin Lu or Daqian Xu. ETHICS DECLARATIONS COMPETING INTERESTS Z.L. owns shares in Signalway Biotechnology

(Pearland, TX), which supplied rabbit antibodies that recognize CLOCK pS106 and PRPS1/2 K29ac. Z.L.’s interest in this company had no bearing on its being chosen to supply these reagents.

The remaining authors declare no competing interests. PEER REVIEW PEER REVIEW INFORMATION _Nature Cell Biology_ thanks Lars Zender, Tsuyoshi Hirota and the other, anonymous, reviewer(s) for

their contribution to the peer review of this work. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps and

institutional affiliations. EXTENDED DATA EXTENDED DATA FIG. 1 CLOCK S106 PHOSPHORYLATION DISASSEMBLES THE CLOCK–BMAL1 COMPLEX. (B-E, H, J, K, M, N) Immunoprecipitation and immunoblotting

with the indicated antibodies was performed. All experiments were repeated at least twice independently. Data are the mean ± SD. (A) The luciferase activity of the indicated cells expressing

a Per1-driven luciferase reporter was measured after IGF1 treatment (12 h) (n = 6). *_P_ < 0.01; **_P_ < 0.001 by One-way ANOVA post hoc test. (B, C, M, N) The indicated cells were

pretreated with or without the indicated inhibitors for 30 min before IGF1 treatment for 30 min (B, C, M) or transfected with the indicated plasmids before IGF1 treatment for 1 h (N). Total

cell lysates and cytosolic fractions were prepared. (D) Flag-CK2α immunoprecipitated from Huh7 cells treated with or without IGF1 for 30 min was incubated with or without CIP for 30 min. (E)

Purified GST-CK2α was mixed with or without active His-ERK2 for _in vitro_ kinase assay, followed by incubation with purified His-CLOCK. Proteins precipitated by GST pulldown assay were

incubated with or without CIP for 30 min. (F) _In vitro_ kinase assays were performed by mixing purified His–CLOCK with or without purified GST-CK2α in the presence of ATP.

Mass-spectrometric analysis was performed. (G) Alignment of CLOCK to the consensus CK2α-phosphorylated substrate motif (SXXD/E). (H, I) Huh7 cells expressing Flag-CLOCK were treated with or

without IGF1 for 1 h (H). Immunoblotting (H) or IHC analyses of human HCC samples (I) were performed with the indicated antibodies and a CLOCK pS106-blocking peptide. (J-L) The indicated

cells expressing the indicated plasmids (J) were treated with or without IGF1 for 1 h (J-L). Total cell lysates and cytosolic and nuclear fractions were prepared (K). The relative CLOCK

abundance was quantified (n = 10) (L). *_P_ < 0.05; ***_P_ < 0.0001 by two-tailed Student’s t test. Source data EXTENDED DATA FIG. 2 CLOCK S106 PHOSPHORYLATION IS REQUIRED FOR ITS

NUCLEAR EXPORTATION. (E-I) Immunoprecipitation and immunoblotting analyses were performed with the indicated antibodies. All experiments were repeated three times independently with similar

results. (A) Alignment of protein sequences spanning CLOCK S106 and the adjacent noncanonical NES from different species. (B, D) MD simulation of CLOCK bound with BMAL1 WT (B) or BMAL1 4Mut

(D144A/D231A/D299A/E303A) (D). Evolution of the backbone root-mean-square-deviation (RMSD) of the CLOCK-BMAL1 complex from the initial frame in 250 ns MD simulations. RMSD of the CLOCK-BMAL1

complex with and without CLOCK S106 phosphorylation are shown in red and black, respectively. (C) The conformation of the CLOCK-BMAL1 complex of the last frame extracted from 250 ns MD

simulation. CLOCK and BMAL1 structures are shown in green and blue, respectively. The red arrow indicates CLOCK S106. D144, D232, D299, and E303 of BMAL1, which are in a close proximity with

CLOCK S106, are shown. (E) Bacterially purified WT GST-CLOCK or GST-CLOCK S106A was incubated with or without His-CK2α in the presence of ATP for an _in vitro_ kinase assay, followed by

incubation with the indicated His-BMAL1 proteins. (F) Huh7 cells stably transfected with the indicated plasmids were treated with or without IGF1 for 1 h. Total cell lysates and cytosolic

fractions were prepared. (G) Huh7 cells were pretreated with or without TBB for 30 min before treatment with or without IGF1 for 1 h. (H) The indicated cells expressing CLOCK shRNA with

reconstituted expression of the indicated CLOCK proteins were harvested. (I) Hep3B cells expressing CLOCK shRNA with reconstituted expression of Flag-rCLOCK proteins were treated with or

without IGF1 for 1 h. Source data EXTENDED DATA FIG. 3 CLOCK ACETYLATES PRPS1/2 K29. (D, J, M) Immunoprecipitation and immunoblotting with the indicated antibodies was performed. All

experiments were repeated at least twice independently. (A) Huh7 cells with or without expression of Flag–CLOCK were treated with or without IGF1 for 1 h. The immunoprecipitated Flag–CLOCK

was eluted with Flag peptide and stained with Coomassie Brilliant Blue after SDS-PAGE. Mass spectrometry-identified protein peptide hits are shown. (B) Purified GST–CLOCK was incubated with

or without His-CK2α and TBB for an _in vitro_ kinase assay, followed by incubation with or without the indicated His-PRPS1/2 proteins in the presence of acetyl-CoA. Mass-spectrometric

analysis was performed. (C) Alignment of protein sequences spanning PRPS1/2 K29 from different species. (D, E) Huh7 cells expressing Flag-PRPS1 were treated with or without IGF1 for 1 h (D).

Immunoblotting analyses (D) or IHC analyses of human HCC samples (E) were performed with the indicated antibodies and a PRPS1/2 K29 acetylation-blocking peptide. (F-J) Genomic DNA was

extracted from two individual clones of the indicated cells with knock-in expression of PRPS1/2 K29R. PCR products amplified from the indicated DNA fragments were shown (F, G) and sequenced

(H, I). The red line indicates the sgRNA-targeting sequence. The black line indicates the PAM. Blue arrows indicate mutated nucleotides. A mutated amino acid and its WT counterpart are

indicated by the solid red box (H, I). These cells were transfected with or without constitutively active IGF1R-CA (J). (K) Purified GST–CLOCK were incubated with or without His-CK2α for an

_in vitro_ kinase assay, followed by incubation with or without the indicated His-PRPS1/2 proteins in the presence of acetyl-CoA. (L, M) Huh7 (L, M) and Hep3B (L) cells expressing CLOCK

shRNA with reconstituted expression of the indicated CLOCK proteins were harvested or (L) treated with or without IGF1 for 1 h (M). Source data EXTENDED DATA FIG. 4 CYTOSOLIC CLOCK PROMOTES

PRPS1/2 STABILIZATION. (A, D-H, J, K, L, O) Immunoprecipitation and immunoblotting with the indicated antibodies was performed. All experiments were repeated three times independently. (A)

The indicated cells were stably transfected with active IGF1R-CA. (B, C) Huh7 cells stimulated with IGF1 for the indicated time (B) or expressing IGF1R-CA (C) were harvested. The mRNA

expression levels of the PRPS1/2 genes were measured using qPCR (n = 6). Data are the mean ± SD. N.S., not significant by One-way ANOVA post hoc test (B) or two-tailed Student’s t test (C).

(D-G) The indicated cells expressing CLOCK shRNA and active IGF1R-CA with reconstituted expression of the indicated CLOCK protein were treated with CHX for the indicated time (D, F). The

quantification of PRPS1/2 levels is shown. Data are the mean ± SD, n = 6, **_P_ < 0.001; ***_P_ < 0.0001 by One-way ANOVA post hoc test (E, G). (H) The indicated cells were treated

with DMSO, MG132 (10 μM), PS341 (10 μM), CQ (25 μM) or bafilomycin A1 (BFA) (10 nM) for 8 h. (I) Alignment of protein sequences spanning PRPS1/2 K29 and the adjacent HSC70 recognized motif

from different species. (J) LAMP2A shRNA was expressed in the indicated cells. (K-N) Huh7 cells expressing PRPS1/2 shRNA with reconstituted expression of the indicated PRPS1/2 proteins were

harvested for immunoblotting (k, l) or qPCR (n = 6) to measure _Prps1/2_ mRNA levels (m, n). Data are the mean ± SD. N.S., not significant by One-way ANOVA post hoc test. (O) Endogenous

CLOCK-depleted Huh7 cells with reconstituted expression of the indicated CLOCK protein were transfected with HA-PRPS1/2 and treated with or without IGF1 for 1 h. Immunoprecipitation using

limited amount of HA antibody was performed. Source data EXTENDED DATA FIG. 5 CLOCK-MEDIATED PRPS1/2 STABILIZATION PROMOTES _DE NOVO_ NUCLEOTIDE SYNTHESIS. (G-L) Immunoprecipitation and

immunoblotting with the indicated antibodies was performed. All experiments were repeated at least twice independently. (A-G) Data are the mean ± SD, n = 6, *_P_ < 0.01; **_P_ < 0.001;

***_P_ < 0.0001; N.S., not significant by One-way ANOVA post hoc test. (A-F) The indicated cells expressing CLOCK shRNA with reconstituted expression of the indicated CLOCK proteins (A,

B, E) or the indicated clones with knock-in expression of PRPS1/2 K29R (C, D, F) were transfected with or without active IGF1R-CA, followed by labeling with D-[6-14C] glucose for 30 min. The

amounts of 14C-RNA (A, C) and 14C-DNA (B, D) were measured. The 13C-labeled PRPP, IMP, AMP, GMP, UMP, and CMP were measured by LC/MS-MS (E, F). (G) Purified GST–CLOCK was incubated with or

without His-CK2α in the presence of ATP for an _in vitro_ kinase assay, followed by incubation with or without the indicated His-PRPS1/2 proteins in the presence of acetyl-CoA. The PRPS1/2

activity was measured. (H, I) Huh7 cells expressing CLOCK shRNA with reconstituted expression of the indicated Flag-rCLOCK were serum-starved for 12 h in the presence of CQ and then treated

with or without EGF (H) or FGF1 (I) for 1 h. Cytosolic and whole cell lysates were harvested. (J) Huh7 cells were stimulated with EGF (100 ng/ml) or FGF1 (25 ng/ml) for the indicated time.

(K) Huh7 cells stably transfected with constitutively active EGFR-vIII or FGFR1-CA were harvested. (L) Huh7 cells expressing CLOCK shRNA and constitutively active EGFR-vIII or FGFR1-CA with

reconstituted expression of the indicated Flag-rCLOCK were treated with CHX for the indicated time. The quantification of PRPS1/2 protein levels is shown. Data are the mean ± SD, **_P_ < 

0.001 by One-way ANOVA post hoc test. Source data EXTENDED DATA FIG. 6 OVEREXPRESSED CK2Α IN HCC CELLS IS CRITICAL FOR CLOCK-ENHANCED PRPS1/2 STABILITY. (A, B, D-L) Immunoprecipitation and

immunoblotting with the indicated antibodies was performed. All experiments were repeated three times independently. (C, D, G, I) Data are the mean ± SD. n = 6, *_P_ < 0.01; **_P_ < 

0.001; ***_P_ < 0.0001 by One-way ANOVA post hoc test. (A, B) The indicated cells expressing CLOCK shRNA with reconstituted expression of the indicated shRNA-resistant CLOCK were

constructed (A) and serum-starved for 12 h in the presence of CQ before treatment with or without IGF1 for 1 h (B). Cytosolic and whole cell lysates were harvested. (C) The indicated cells

with reconstituted expression of the indicated CLOCK proteins were treated with or without IGF1 for 12 h, followed by labeling with D-[6-14C] glucose for 30 min. The amounts of 14C-RNA and

14C-DNA were measured. (D) The indicated cells expressing CLOCK shRNA and IGF1R-CA with reconstituted expression of Flag-rCLOCK were treated with CHX for the indicated time. The

quantification of PRPS1/2 levels is shown. (E, F) The indicated cells were treated with or without IGF1 for 1 h. Whole cell lysates were harvested. (G) L02 cells transfected with the

indicated plasmids were treated with CHX for the indicated time in the presence or absence of IGF1. The quantification of PRPS1/2 levels is shown. (H) Huh7 cells transfected with the

indicated shRNA were treated with or without IGF1 for 1 h. (I) Huh7 cells transfected with the indicated shRNA were treated with CHX for the indicated time in the presence or absence of

IGF1. The quantification of PRPS1/2 levels is shown. Source data EXTENDED DATA FIG. 7 BOTH NUCLEAR TRANSCRIPTIONAL ACTIVITY AND CYTOSOLIC FUNCTION OF CLOCK CONTRIBUTE TO HCC CELL

PROLIFERATION. (A, D, E, I, J, L, M) Immunoprecipitation and immunoblotting with the indicated antibodies was performed. All experiments were repeated at least twice independently. (A-C,

E-G, H, J, K, N) Data are the mean ± SD. *_P_ < 0.01; **_P_ < 0.001; ***_P_ < 0.0001 by One-way ANOVA post hoc test. (A-C) The indicated cells stably transfected with the indicated

plasmids and shRNA were constructed (A) and transiently expressed a Per1-driven luciferase reporter before IGF1 treatment for 12 h. The luciferase activity is shown (n = 6). The mRNA levels

of CLOCK-downstream target genes were measured using qPCR (n = 6) (C). Cytosolic and whole cell lysates from Huh7 cells were harvested (D). (E) Huh7 cells transfected with the indicated

plasmids and shRNA were treated with CHX. PRPS1/2 protein was quantified (n = 6). (F, G) The indicated cells transfected with the indicated plasmids and shRNA were labeled with D-[6-14C]

glucose. The amounts of 14C-RNA (F) and 14C-DNA (G) were measured (n = 6). (H) The indicated cells transfected with the indicated plasmids and shRNA were plated in complete culture medium

and counted (n = 6). (I) Huh7 cells were pretreated with or without different dose of Sorafenib for 30 min before IGF1 treatment for 1 h. (J, K) The indicated cells expressing CLOCK shRNA

and active IGF1R-CA with reconstituted expression of Flag-rCLOCK WT or S106D were treated with CHX (J) or without CHX (K) in the presence or absence of Sorafenib for the indicted time.

PRPS1/2 protein quantification (J) and cell counting (K) were performed (n = 6). (L-N) The indicated cells with reconstituted expression of Flag-rCLOCK WT or S106D were harvested (L) or

treated with CHX (M) or without CHX (N) for the indicated time. PRPS1/2 protein quantification (M) and cell counting (N) were performed (n = 6). Source data EXTENDED DATA FIG. 8

CLOCK-MEDIATED PRPS1/2 STABILIZATION PROMOTES HCC CELL PROLIFERATION AND LIVER TUMOR GROWTH. (A, B) Huh7 cells (1 × 106) expressing CLOCK shRNA with reconstituted expression of the indicated

CLOCK proteins (A) expressing WT PRPS1/2 or PRPS1/2 K29R knock-in mutants (B) were subcutaneously injected into athymic nude mice (n = 6 per group). The mice were euthanized and examined

for tumor growth 28 days after injection. Tumor volumes were calculated, and the tumors were weighed. Data are the mean ± SD, n = 7, *_P_ < 0.01; **_P_ < 0.001 by One-way ANOVA post

hoc test. (C, D) IHC analyses of the indicated tumor samples were performed with an anti-Ki67 antibody. Ki67-positive cells were quantified. Data are the mean ± SD, n = 10, ***_P_ < 

0.0001 by One-way ANOVA post hoc test. (E, F) TUNEL analyses of the indicated tumor samples were performed (upper). Apoptotic cells were stained brown and quantified in n = 10 microscopic

fields (lower). Data are the mean ± SD, ***_P_ < 0.0001 by One-way ANOVA post hoc test. (G) Huh7 cells (1 × 106) expressing CLOCK shRNA with reconstituted expression of the indicated

CLOCK proteins were intrahepatically injected into athymic nude mice (n = 6 per group). The mice were euthanized and examined for tumor growth 22 days after injection. The arrows indicate

tumors (left). The tumor volumes were measured (right). Data are the mean ± SD, n = 6, *_P_ < 0.01 by two-tailed Student’s t test. (H) Huh7 cells (1 × 106) expressing CLOCK shRNA with

reconstituted expression of the indicated CLOCK proteins were subcutaneously injected into athymic nude mice (n = 7 per group). The resulting tumors were resected 22 days after injection

(left). The growth of xenografted tumors in the mice was measured (middle) and the tumors were weighed (right). Data are the mean ± SD, **_P_ < 0.001 by two-tailed Student’s t test.

Source data SUPPLEMENTARY INFORMATION REPORTING SUMMARY SOURCE DATA SOURCE DATA FIG. 1 Unprocessed WBs. SOURCE DATA FIG. 2 Unprocessed WBs. SOURCE DATA FIG. 3 Unprocessed WBs. SOURCE DATA

FIG. 4 Unprocessed WBs. SOURCE DATA EXTENDED DATA FIG. 1 Unprocessed WB. SOURCE DATA EXTENDED DATA FIG. 2 Unprocessed WBs. SOURCE DATA EXTENDED DATA FIG. 3 Unprocessed WB. SOURCE DATA

EXTENDED DATA FIG. 4 Unprocessed WBs. SOURCE DATA EXTENDED DATA FIG. 5 Unprocessed WB. SOURCE DATA EXTENDED DATA FIG. 6 Unprocessed WBs. SOURCE DATA EXTENDED DATA FIG. 7 Unprocessed WBs.

SOURCE DATA TABLE FIG. 1 Statistical source data. SOURCE DATA TABLE FIG. 2 Statistical source data. SOURCE DATA TABLE FIG. 4 Statistical source data. SOURCE DATA TABLE FIG. 5 Statistical

source data. SOURCE DATA TABLE FIG. 6 Statistical source data. SOURCE DATA TABLE FIG. 7 Statistical source data. SOURCE DATA EXTENDED DATA FIG. 1 Statistical source data for Extended Data

Fig. 1. SOURCE DATA EXTENDED DATA FIG. 4 Statistical source data for Extended Data Fig. 4. SOURCE DATA EXTENDED DATA FIG. 5 Statistical source data for Extended Data Fig. 5. SOURCE DATA

EXTENDED DATA FIG. 6 Statistical source data for Extended Data Fig. 6. SOURCE DATA EXTENDED DATA FIG. 7 Statistical source data for Extended Data Fig. 7. SOURCE DATA EXTENDED DATA FIG. 8

Statistical source data for Extended Data Fig. 8. RIGHTS AND PERMISSIONS Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a

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agreement and applicable law. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Liu, T., Wang, Z., Ye, L. _et al._ Nucleus-exported CLOCK acetylates PRPS to promote de novo

nucleotide synthesis and liver tumour growth. _Nat Cell Biol_ 25, 273–284 (2023). https://doi.org/10.1038/s41556-022-01061-0 Download citation * Received: 28 February 2022 * Accepted: 24

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