PTEN regulates RPA1 and protects DNA replication forks

Wang, G; Li, Y; Wang, P; Liang, H; Cui, M; Zhu, M; Guo, L; Su, Q; Sun, Y; Mcnutt, MA; Yin, Y

PTEN regulates RPA1 and protects DNA replication forks

Wang, G Li, Y Wang, P Liang, H Cui, M Zhu, M Guo, L Su, Q

Sun, Y Mcnutt, MA Yin, Y

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Publication Type:: Journal Article
Citation:: Cell Research, 2015, 25 (11), pp. 1189 - 1204
Issue Date:: 2015-01-01

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Field	Value	Language
dc.contributor.author	Wang, G	en_US
dc.contributor.author	Li, Y	en_US
dc.contributor.author	Wang, P	en_US
dc.contributor.author	Liang, H	en_US
dc.contributor.author	Cui, M	en_US
dc.contributor.author	Zhu, M	en_US
dc.contributor.author	Guo, L	en_US
dc.contributor.author	Su, Q https://orcid.org/0000-0001-7364-3945	en_US
dc.contributor.author	Sun, Y	en_US
dc.contributor.author	Mcnutt, MA	en_US
dc.contributor.author	Yin, Y	en_US
dc.date.available	2015-07-31	en_US
dc.date.issued	2015-01-01	en_US
dc.identifier.citation	Cell Research, 2015, 25 (11), pp. 1189 - 1204	en_US
dc.identifier.issn	1001-0602	en_US
dc.identifier.uri	http://hdl.handle.net/10453/119467
dc.description.abstract	© 2015 IBCB, SIBS, CAS. Tumor suppressor PTEN regulates cellular activities and controls genome stability through multiple mechanisms. In this study, we report that PTEN is necessary for the protection of DNA replication forks against replication stress. We show that deletion of PTEN leads to replication fork collapse and chromosomal instability upon fork stalling following nucleotide depletion induced by hydroxyurea. PTEN is physically associated with replication protein A 1 (RPA1) via the RPA1 C-terminal domain. STORM and iPOND reveal that PTEN is localized at replication sites and promotes RPA1 accumulation on replication forks. PTEN recruits the deubiquitinase OTUB1 to mediate RPA1 deubiquitination. RPA1 deletion confers a phenotype like that observed in PTEN knockout cells with stalling of replication forks. Expression of PTEN and RPA1 shows strong correlation in colorectal cancer. Heterozygous disruption of RPA1 promotes tumorigenesis in mice. These results demonstrate that PTEN is essential for DNA replication fork protection. We propose that RPA1 is a target of PTEN function in fork protection and that PTEN maintains genome stability through regulation of DNA replication.	en_US
dc.relation.ispartof	Cell Research	en_US
dc.relation.isbasedon	10.1038/cr.2015.115	en_US
dc.subject.classification	Developmental Biology	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Chromosomal Instability	en_US
dc.subject.mesh	Genomic Instability	en_US
dc.subject.mesh	DNA Replication	en_US
dc.subject.mesh	Replication Protein A	en_US
dc.title	PTEN regulates RPA1 and protects DNA replication forks	en_US
dc.type	Journal Article
utslib.citation.volume	11	en_US
utslib.citation.volume	25	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
utslib.for	1103 Clinical Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences
utslib.copyright.status	closed_access
pubs.issue	11	en_US
pubs.publication-status	Published	en_US
pubs.volume	25	en_US

Abstract:

© 2015 IBCB, SIBS, CAS. Tumor suppressor PTEN regulates cellular activities and controls genome stability through multiple mechanisms. In this study, we report that PTEN is necessary for the protection of DNA replication forks against replication stress. We show that deletion of PTEN leads to replication fork collapse and chromosomal instability upon fork stalling following nucleotide depletion induced by hydroxyurea. PTEN is physically associated with replication protein A 1 (RPA1) via the RPA1 C-terminal domain. STORM and iPOND reveal that PTEN is localized at replication sites and promotes RPA1 accumulation on replication forks. PTEN recruits the deubiquitinase OTUB1 to mediate RPA1 deubiquitination. RPA1 deletion confers a phenotype like that observed in PTEN knockout cells with stalling of replication forks. Expression of PTEN and RPA1 shows strong correlation in colorectal cancer. Heterozygous disruption of RPA1 promotes tumorigenesis in mice. These results demonstrate that PTEN is essential for DNA replication fork protection. We propose that RPA1 is a target of PTEN function in fork protection and that PTEN maintains genome stability through regulation of DNA replication.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/119467