Evading immune surveillance via tyrosine phosphorylation of nuclear PCNA

Yuan Liang Wang; Chuan Chun Lee; Yi Chun Shen; Pei Le Lin; Wan Rong Wu; You Zhe Lin; Wei Chung Cheng; Han Chang; Yu Hung; Yi Chun Cho; Liang Chih Liu; Wei Ya Xia; Jin Huei Ji; Ji An Liang; Shu Fen Chiang; Chang Gong Liu; Jun Yao; Mien Chie Hung; Shao Chun Wang

doi:10.1016/j.celrep.2021.109537

Evading immune surveillance via tyrosine phosphorylation of nuclear PCNA

Yuan Liang Wang, Chuan Chun Lee, Yi Chun Shen, Pei Le Lin, Wan Rong Wu, You Zhe Lin, Wei Chung Cheng, Han Chang, Yu Hung, Yi Chun Cho, Liang Chih Liu, Wei Ya Xia, Jin Huei Ji, Ji An Liang, Shu Fen Chiang, Chang Gong Liu, Jun Yao, Mien Chie Hung, Shao Chun Wang

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

Increased DNA replication and metastasis are hallmarks of cancer progression, while deregulated proliferation often triggers sustained replication stresses in cancer cells. How cancer cells overcome the growth stress and proceed to metastasis remains largely elusive. Proliferating cell nuclear antigen (PCNA) is an indispensable component of the DNA replication machinery. Here, we show that phosphorylation of PCNA on tyrosine 211 (pY211-PCNA) regulates DNA metabolism and tumor microenvironment. Abrogation of pY211-PCNA blocks fork processivity, resulting in biogenesis of single-stranded DNA (ssDNA) through a MRE11-dependent mechanism. The cytosolic ssDNA subsequently induces inflammatory cytokines through a cyclic GMP-AMP synthetase (cGAS)-dependent cascade, triggering an anti-tumor immunity by natural killer (NK) cells to suppress distant metastasis. Expression of pY211-PCNA is inversely correlated with cytosolic ssDNA and associated with poor survival in patients with cancer. Our results pave the way to biomarkers and therapies exploiting immune responsiveness to target metastatic cancer.

Original language	English (US)
Article number	109537
Journal	Cell Reports
Volume	36
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2021.109537
State	Published - Aug 24 2021

Keywords

PCNA
cGAS
innate immune response
pY211 PCNA
ssDNA
type I interferon

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2021.109537

Cite this

Wang, Y. L., Lee, C. C., Shen, Y. C., Lin, P. L., Wu, W. R., Lin, Y. Z., Cheng, W. C., Chang, H., Hung, Y., Cho, Y. C., Liu, L. C., Xia, W. Y., Ji, J. H., Liang, J. A., Chiang, S. F., Liu, C. G., Yao, J., Hung, M. C., & Wang, S. C. (2021). Evading immune surveillance via tyrosine phosphorylation of nuclear PCNA. Cell Reports, 36(8), Article 109537. https://doi.org/10.1016/j.celrep.2021.109537

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abstract = "Increased DNA replication and metastasis are hallmarks of cancer progression, while deregulated proliferation often triggers sustained replication stresses in cancer cells. How cancer cells overcome the growth stress and proceed to metastasis remains largely elusive. Proliferating cell nuclear antigen (PCNA) is an indispensable component of the DNA replication machinery. Here, we show that phosphorylation of PCNA on tyrosine 211 (pY211-PCNA) regulates DNA metabolism and tumor microenvironment. Abrogation of pY211-PCNA blocks fork processivity, resulting in biogenesis of single-stranded DNA (ssDNA) through a MRE11-dependent mechanism. The cytosolic ssDNA subsequently induces inflammatory cytokines through a cyclic GMP-AMP synthetase (cGAS)-dependent cascade, triggering an anti-tumor immunity by natural killer (NK) cells to suppress distant metastasis. Expression of pY211-PCNA is inversely correlated with cytosolic ssDNA and associated with poor survival in patients with cancer. Our results pave the way to biomarkers and therapies exploiting immune responsiveness to target metastatic cancer.",

keywords = "PCNA, cGAS, innate immune response, pY211 PCNA, ssDNA, type I interferon",

author = "Wang, {Yuan Liang} and Lee, {Chuan Chun} and Shen, {Yi Chun} and Lin, {Pei Le} and Wu, {Wan Rong} and Lin, {You Zhe} and Cheng, {Wei Chung} and Han Chang and Yu Hung and Cho, {Yi Chun} and Liu, {Liang Chih} and Xia, {Wei Ya} and Ji, {Jin Huei} and Liang, {Ji An} and Chiang, {Shu Fen} and Liu, {Chang Gong} and Jun Yao and Hung, {Mien Chie} and Wang, {Shao Chun}",

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AU - Wang, Yuan Liang

AU - Lee, Chuan Chun

AU - Shen, Yi Chun

AU - Lin, Pei Le

AU - Wu, Wan Rong

AU - Lin, You Zhe

AU - Cheng, Wei Chung

AU - Chang, Han

AU - Hung, Yu

AU - Cho, Yi Chun

AU - Liu, Liang Chih

AU - Xia, Wei Ya

AU - Ji, Jin Huei

AU - Liang, Ji An

AU - Chiang, Shu Fen

AU - Liu, Chang Gong

AU - Yao, Jun

AU - Hung, Mien Chie

AU - Wang, Shao Chun

PY - 2021/8/24

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N2 - Increased DNA replication and metastasis are hallmarks of cancer progression, while deregulated proliferation often triggers sustained replication stresses in cancer cells. How cancer cells overcome the growth stress and proceed to metastasis remains largely elusive. Proliferating cell nuclear antigen (PCNA) is an indispensable component of the DNA replication machinery. Here, we show that phosphorylation of PCNA on tyrosine 211 (pY211-PCNA) regulates DNA metabolism and tumor microenvironment. Abrogation of pY211-PCNA blocks fork processivity, resulting in biogenesis of single-stranded DNA (ssDNA) through a MRE11-dependent mechanism. The cytosolic ssDNA subsequently induces inflammatory cytokines through a cyclic GMP-AMP synthetase (cGAS)-dependent cascade, triggering an anti-tumor immunity by natural killer (NK) cells to suppress distant metastasis. Expression of pY211-PCNA is inversely correlated with cytosolic ssDNA and associated with poor survival in patients with cancer. Our results pave the way to biomarkers and therapies exploiting immune responsiveness to target metastatic cancer.

AB - Increased DNA replication and metastasis are hallmarks of cancer progression, while deregulated proliferation often triggers sustained replication stresses in cancer cells. How cancer cells overcome the growth stress and proceed to metastasis remains largely elusive. Proliferating cell nuclear antigen (PCNA) is an indispensable component of the DNA replication machinery. Here, we show that phosphorylation of PCNA on tyrosine 211 (pY211-PCNA) regulates DNA metabolism and tumor microenvironment. Abrogation of pY211-PCNA blocks fork processivity, resulting in biogenesis of single-stranded DNA (ssDNA) through a MRE11-dependent mechanism. The cytosolic ssDNA subsequently induces inflammatory cytokines through a cyclic GMP-AMP synthetase (cGAS)-dependent cascade, triggering an anti-tumor immunity by natural killer (NK) cells to suppress distant metastasis. Expression of pY211-PCNA is inversely correlated with cytosolic ssDNA and associated with poor survival in patients with cancer. Our results pave the way to biomarkers and therapies exploiting immune responsiveness to target metastatic cancer.

KW - PCNA

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KW - innate immune response

KW - pY211 PCNA

KW - ssDNA

KW - type I interferon

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Evading immune surveillance via tyrosine phosphorylation of nuclear PCNA

Abstract

Keywords

ASJC Scopus subject areas

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