PCNA Ubiquitination Is Important, But Not Essential for Translesion DNA Synthesis in Mammalian Cells

Translesion DNA synthesis (TLS) is a DNA damage tolerance mechanism in which specialized low-fidelity DNA polymerases bypass replication-blocking lesions, and it is usually associated with mutagenesis. In Saccharomyces cerevisiae a key event in TLS is the monoubiquitination of PCNA, which enables re...

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Published in:	PLoS genetics Vol. 7; no. 9; p. e1002262
Main Authors:	Hendel, Ayal, Krijger, Peter H. L., Diamant, Noam, Goren, Zohar, Langerak, Petra, Kim, Jungmin, Reißner, Thomas, Lee, Kyoo-young, Geacintov, Nicholas E., Carell, Thomas, Myung, Kyungjae, Tateishi, Satoshi, D'Andrea, Alan, Jacobs, Heinz, Livneh, Zvi
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 01.09.2011 Public Library of Science (PLoS)
Subjects:	Animals Biology Biomedical research Brewer's yeast Cancer Cisplatin - pharmacology Cyclin-dependent kinases Deoxyribonucleic acid DNA DNA - biosynthesis DNA - drug effects DNA - genetics DNA Damage DNA Repair DNA Replication DNA synthesis DNA, Single-Stranded - biosynthesis DNA, Single-Stranded - genetics E coli Experiments Genetic aspects Mice Mutagenesis Mutation Physiological aspects Plasmids Proliferating Cell Nuclear Antigen - genetics Proliferating Cell Nuclear Antigen - metabolism Proteins Ubiquitin - genetics Ubiquitin - metabolism Ubiquitin-proteasome system Ubiquitination Ultraviolet Rays Japan
ISSN:	1553-7404, 1553-7390, 1553-7404
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Abstract	Translesion DNA synthesis (TLS) is a DNA damage tolerance mechanism in which specialized low-fidelity DNA polymerases bypass replication-blocking lesions, and it is usually associated with mutagenesis. In Saccharomyces cerevisiae a key event in TLS is the monoubiquitination of PCNA, which enables recruitment of the specialized polymerases to the damaged site through their ubiquitin-binding domain. In mammals, however, there is a debate on the requirement for ubiquitinated PCNA (PCNA-Ub) in TLS. We show that UV-induced Rpa foci, indicative of single-stranded DNA (ssDNA) regions caused by UV, accumulate faster and disappear more slowly in Pcna(K164R/K164R) cells, which are resistant to PCNA ubiquitination, compared to Pcna(+/+) cells, consistent with a TLS defect. Direct analysis of TLS in these cells, using gapped plasmids with site-specific lesions, showed that TLS is strongly reduced across UV lesions and the cisplatin-induced intrastrand GG crosslink. A similar effect was obtained in cells lacking Rad18, the E3 ubiquitin ligase which monoubiquitinates PCNA. Consistently, cells lacking Usp1, the enzyme that de-ubiquitinates PCNA exhibited increased TLS across a UV lesion and the cisplatin adduct. In contrast, cells lacking the Rad5-homologs Shprh and Hltf, which polyubiquitinate PCNA, exhibited normal TLS. Knocking down the expression of the TLS genes Rev3L, PolH, or Rev1 in Pcna(K164R/K164R) mouse embryo fibroblasts caused each an increased sensitivity to UV radiation, indicating the existence of TLS pathways that are independent of PCNA-Ub. Taken together these results indicate that PCNA-Ub is required for maximal TLS. However, TLS polymerases can be recruited to damaged DNA also in the absence of PCNA-Ub, and perform TLS, albeit at a significantly lower efficiency and altered mutagenic specificity.
AbstractList	Translesion DNA synthesis (TLS) is a DNA damage tolerance mechanism in which specialized low-fidelity DNA polymerases bypass replication-blocking lesions, and it is usually associated with mutagenesis. In Saccharomyces cerevisiae a key event in TLS is the monoubiquitination of PCNA, which enables recruitment of the specialized polymerases to the damaged site through their ubiquitin-binding domain. In mammals, however, there is a debate on the requirement for ubiquitinated PCNA (PCNA-Ub) in TLS. We show that UV-induced Rpa foci, indicative of single- stranded DNA (ssDNA) regions caused by UV, accumulate faster and disappear more slowly in [Pcna.sup.K164R/K164R] cells, which are resistant to PCNA ubiquitination, compared to [Pcna.sup.+/+] cells, consistent with a TLS defect. Direct analysis of TLS in these cells, using gapped plasmids with site-specific lesions, showed that TLS is strongly reduced across UV lesions and the cisplatin-induced intrastrand GG crosslink. A similar effect was obtained in cells lacking Rad18, the E3 ubiquitin ligase which monoubiquitinates PCNA. Consistently, cells lacking Usp1, the enzyme that de-ubiquitinates PCNA exhibited increased TLS across a UV lesion and the cisplatin adduct. In contrast, cells lacking the Rad5-homologs Shprh and Hltf, which polyubiquitinate PCNA, exhibited normal TLS. Knocking down the expression of the TLS genes Rev3L, PolH,or Rev1 in [Pcna.sup.K164R/K164R] mouse embryo fibroblasts caused each an increased sensitivity to UV radiation, indicating the existence of TLS pathways that are independent of PCNA-Ub. Taken together these results indicate that PCNA-Ub is required for maximal TLS. However, TLS polymerases can be recruited to damaged DNA also in the absence of PCNA-Ub, and perform TLS, albeit at a significantly lower efficiency and altered mutagenic specificity. Translesion DNA synthesis (TLS) is a DNA damage tolerance mechanism in which specialized low-fidelity DNA polymerases bypass replication-blocking lesions, and it is usually associated with mutagenesis. In Saccharomyces cerevisiae a key event in TLS is the monoubiquitination of PCNA, which enables recruitment of the specialized polymerases to the damaged site through their ubiquitin-binding domain. In mammals, however, there is a debate on the requirement for ubiquitinated PCNA (PCNA-Ub) in TLS. We show that UV-induced Rpa foci, indicative of single-stranded DNA (ssDNA) regions caused by UV, accumulate faster and disappear more slowly in PcnaK164R/K164R cells, which are resistant to PCNA ubiquitination, compared to Pcna+/+ cells, consistent with a TLS defect. Direct analysis of TLS in these cells, using gapped plasmids with site-specific lesions, showed that TLS is strongly reduced across UV lesions and the cisplatin-induced intrastrand GG crosslink. A similar effect was obtained in cells lacking Rad18, the E3 ubiquitin ligase which monoubiquitinates PCNA. Consistently, cells lacking Usp1, the enzyme that de-ubiquitinates PCNA exhibited increased TLS across a UV lesion and the cisplatin adduct. In contrast, cells lacking the Rad5-homologs Shprh and Hltf, which polyubiquitinate PCNA, exhibited normal TLS. Knocking down the expression of the TLS genes Rev3L, PolH, or Rev1 in PcnaK164R/K164R mouse embryo fibroblasts caused each an increased sensitivity to UV radiation, indicating the existence of TLS pathways that are independent of PCNA-Ub. Taken together these results indicate that PCNA-Ub is required for maximal TLS. However, TLS polymerases can be recruited to damaged DNA also in the absence of PCNA-Ub, and perform TLS, albeit at a significantly lower efficiency and altered mutagenic specificity. Translesion DNA synthesis (TLS) is a DNA damage tolerance mechanism in which specialized low-fidelity DNA polymerases bypass replication-blocking lesions, and it is usually associated with mutagenesis. In Saccharomyces cerevisiae a key event in TLS is the monoubiquitination of PCNA, which enables recruitment of the specialized polymerases to the damaged site through their ubiquitin-binding domain. In mammals, however, there is a debate on the requirement for ubiquitinated PCNA (PCNA-Ub) in TLS. We show that UV-induced Rpa foci, indicative of single-stranded DNA (ssDNA) regions caused by UV, accumulate faster and disappear more slowly in Pcna(K164R/K164R) cells, which are resistant to PCNA ubiquitination, compared to Pcna(+/+) cells, consistent with a TLS defect. Direct analysis of TLS in these cells, using gapped plasmids with site-specific lesions, showed that TLS is strongly reduced across UV lesions and the cisplatin-induced intrastrand GG crosslink. A similar effect was obtained in cells lacking Rad18, the E3 ubiquitin ligase which monoubiquitinates PCNA. Consistently, cells lacking Usp1, the enzyme that de-ubiquitinates PCNA exhibited increased TLS across a UV lesion and the cisplatin adduct. In contrast, cells lacking the Rad5-homologs Shprh and Hltf, which polyubiquitinate PCNA, exhibited normal TLS. Knocking down the expression of the TLS genes Rev3L, PolH, or Rev1 in Pcna(K164R/K164R) mouse embryo fibroblasts caused each an increased sensitivity to UV radiation, indicating the existence of TLS pathways that are independent of PCNA-Ub. Taken together these results indicate that PCNA-Ub is required for maximal TLS. However, TLS polymerases can be recruited to damaged DNA also in the absence of PCNA-Ub, and perform TLS, albeit at a significantly lower efficiency and altered mutagenic specificity.Translesion DNA synthesis (TLS) is a DNA damage tolerance mechanism in which specialized low-fidelity DNA polymerases bypass replication-blocking lesions, and it is usually associated with mutagenesis. In Saccharomyces cerevisiae a key event in TLS is the monoubiquitination of PCNA, which enables recruitment of the specialized polymerases to the damaged site through their ubiquitin-binding domain. In mammals, however, there is a debate on the requirement for ubiquitinated PCNA (PCNA-Ub) in TLS. We show that UV-induced Rpa foci, indicative of single-stranded DNA (ssDNA) regions caused by UV, accumulate faster and disappear more slowly in Pcna(K164R/K164R) cells, which are resistant to PCNA ubiquitination, compared to Pcna(+/+) cells, consistent with a TLS defect. Direct analysis of TLS in these cells, using gapped plasmids with site-specific lesions, showed that TLS is strongly reduced across UV lesions and the cisplatin-induced intrastrand GG crosslink. A similar effect was obtained in cells lacking Rad18, the E3 ubiquitin ligase which monoubiquitinates PCNA. Consistently, cells lacking Usp1, the enzyme that de-ubiquitinates PCNA exhibited increased TLS across a UV lesion and the cisplatin adduct. In contrast, cells lacking the Rad5-homologs Shprh and Hltf, which polyubiquitinate PCNA, exhibited normal TLS. Knocking down the expression of the TLS genes Rev3L, PolH, or Rev1 in Pcna(K164R/K164R) mouse embryo fibroblasts caused each an increased sensitivity to UV radiation, indicating the existence of TLS pathways that are independent of PCNA-Ub. Taken together these results indicate that PCNA-Ub is required for maximal TLS. However, TLS polymerases can be recruited to damaged DNA also in the absence of PCNA-Ub, and perform TLS, albeit at a significantly lower efficiency and altered mutagenic specificity. Translesion DNA synthesis (TLS) is a DNA damage tolerance mechanism in which specialized low-fidelity DNA polymerases bypass replication-blocking lesions, and it is usually associated with mutagenesis. In Saccharomyces cerevisiae a key event in TLS is the monoubiquitination of PCNA, which enables recruitment of the specialized polymerases to the damaged site through their ubiquitin-binding domain. In mammals, however, there is a debate on the requirement for ubiquitinated PCNA (PCNA-Ub) in TLS. We show that UV-induced Rpa foci, indicative of single-stranded DNA (ssDNA) regions caused by UV, accumulate faster and disappear more slowly in Pcna(K164R/K164R) cells, which are resistant to PCNA ubiquitination, compared to Pcna(+/+) cells, consistent with a TLS defect. Direct analysis of TLS in these cells, using gapped plasmids with site-specific lesions, showed that TLS is strongly reduced across UV lesions and the cisplatin-induced intrastrand GG crosslink. A similar effect was obtained in cells lacking Rad18, the E3 ubiquitin ligase which monoubiquitinates PCNA. Consistently, cells lacking Usp1, the enzyme that de-ubiquitinates PCNA exhibited increased TLS across a UV lesion and the cisplatin adduct. In contrast, cells lacking the Rad5-homologs Shprh and Hltf, which polyubiquitinate PCNA, exhibited normal TLS. Knocking down the expression of the TLS genes Rev3L, PolH, or Rev1 in Pcna(K164R/K164R) mouse embryo fibroblasts caused each an increased sensitivity to UV radiation, indicating the existence of TLS pathways that are independent of PCNA-Ub. Taken together these results indicate that PCNA-Ub is required for maximal TLS. However, TLS polymerases can be recruited to damaged DNA also in the absence of PCNA-Ub, and perform TLS, albeit at a significantly lower efficiency and altered mutagenic specificity. Translesion DNA synthesis (TLS) is a DNA damage tolerance mechanism in which specialized low-fidelity DNA polymerases bypass replication-blocking lesions, and it is usually associated with mutagenesis. In Saccharomyces cerevisiae a key event in TLS is the monoubiquitination of PCNA, which enables recruitment of the specialized polymerases to the damaged site through their ubiquitin-binding domain. In mammals, however, there is a debate on the requirement for ubiquitinated PCNA (PCNA-Ub) in TLS. We show that UV-induced Rpa foci, indicative of single-stranded DNA (ssDNA) regions caused by UV, accumulate faster and disappear more slowly in PcnaK164R/K164R cells, which are resistant to PCNA ubiquitination, compared to Pcna+/+ cells, consistent with a TLS defect. Direct analysis of TLS in these cells, using gapped plasmids with site-specific lesions, showed that TLS is strongly reduced across UV lesions and the cisplatin-induced intrastrand GG crosslink. A similar effect was obtained in cells lacking Rad18, the E3 ubiquitin ligase which monoubiquitinates PCNA. Consistently, cells lacking Usp1, the enzyme that de-ubiquitinates PCNA exhibited increased TLS across a UV lesion and the cisplatin adduct. In contrast, cells lacking the Rad5-homologs Shprh and Hltf, which polyubiquitinate PCNA, exhibited normal TLS. Knocking down the expression of the TLS genes Rev3L, PolH, or Rev1 in PcnaK164R/K164R mouse embryo fibroblasts caused each an increased sensitivity to UV radiation, indicating the existence of TLS pathways that are independent of PCNA-Ub. Taken together these results indicate that PCNA-Ub is required for maximal TLS. However, TLS polymerases can be recruited to damaged DNA also in the absence of PCNA-Ub, and perform TLS, albeit at a significantly lower efficiency and altered mutagenic specificity. DNA damage can block replication and lead to mutations, genomic instability, and cancer. In cases when the removal of DNA damage and restoration of the original sequence prior to replication is impossible, cells utilize DNA damage tolerance mechanisms, which help replication to bypass the lesions. A major universal tolerance mechanism is translesion DNA synthesis (TLS), in which specialized low-fidelity DNA polymerases elongate the DNA across the lesion. This is a double-edged sword because the price of completing replication is an increased risk of point mutations opposite the lesion. Thus, TLS regulation is critical for preventing an escalation in mutation rates. A key element in TLS regulation is the attachment of a small protein called ubiquitin to the PCNA protein, a sliding DNA clamp that tethers the DNA polymerases to DNA, which functions to recruit the TLS DNA polymerase to the damaged site in DNA. While in yeast this modification of PCNA is crucial for TLS, there is a debate about its importance in mammals. Here we show that in mammalian cells the modification of PCNA by ubiquitin is important, but there exist secondary yet significant TLS mechanisms that operate in its absence and have an altered mutational outcome.
Audience	Academic
Author	Diamant, Noam Geacintov, Nicholas E. Tateishi, Satoshi Krijger, Peter H. L. Goren, Zohar Langerak, Petra Carell, Thomas Myung, Kyungjae Kim, Jungmin D'Andrea, Alan Jacobs, Heinz Reißner, Thomas Lee, Kyoo-young Hendel, Ayal Livneh, Zvi
AuthorAffiliation	4 Department of Chemistry and Biochemistry, Ludwig Maximilians-University Munich, Munich, Germany 5 Genome Instability Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America 6 Chemistry Department, New York University, New York, United States of America 1 Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel University of Washington, United States of America 7 Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan 2 Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands 3 Department of Radiation Oncology and Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America
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BackLink	https://www.ncbi.nlm.nih.gov/pubmed/21931560$$D View this record in MEDLINE/PubMed
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ContentType	Journal Article
Copyright	COPYRIGHT 2011 Public Library of Science 2011 2011 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Citation: Hendel A, Krijger PHL, Diamant N, Goren Z, Langerak P, et al. (2011) PCNA Ubiquitination Is Important, But Not Essential for Translesion DNA Synthesis in Mammalian Cells. PLoS Genet 7(9): e1002262. doi:10.1371/journal.pgen.1002262
Copyright_xml	– notice: COPYRIGHT 2011 Public Library of Science – notice: 2011 – notice: 2011 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Citation: Hendel A, Krijger PHL, Diamant N, Goren Z, Langerak P, et al. (2011) PCNA Ubiquitination Is Important, But Not Essential for Translesion DNA Synthesis in Mammalian Cells. PLoS Genet 7(9): e1002262. doi:10.1371/journal.pgen.1002262
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Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Conceived and designed the experiments: AH PHLK ND ZG. Performed the experiments: AH PHLK ND ZG. Analyzed the data: AH PHLK ND ZG HJ ZL. Contributed reagents/materials/analysis tools: PL JK TR KL NEG TC KM ST AD HJ. Wrote the paper: ZL AH. These authors also contributed equally to this work.
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Snippet	Translesion DNA synthesis (TLS) is a DNA damage tolerance mechanism in which specialized low-fidelity DNA polymerases bypass replication-blocking lesions, and... Translesion DNA synthesis (TLS) is a DNA damage tolerance mechanism in which specialized low-fidelity DNA polymerases bypass replication-blocking lesions,...
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StartPage	e1002262
SubjectTerms	Animals Biology Biomedical research Brewer's yeast Cancer Cisplatin - pharmacology Cyclin-dependent kinases Deoxyribonucleic acid DNA DNA - biosynthesis DNA - drug effects DNA - genetics DNA Damage DNA Repair DNA Replication DNA synthesis DNA, Single-Stranded - biosynthesis DNA, Single-Stranded - genetics E coli Experiments Genetic aspects Mice Mutagenesis Mutation Physiological aspects Plasmids Proliferating Cell Nuclear Antigen - genetics Proliferating Cell Nuclear Antigen - metabolism Proteins Ubiquitin - genetics Ubiquitin - metabolism Ubiquitin-proteasome system Ubiquitination Ultraviolet Rays
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Title	PCNA Ubiquitination Is Important, But Not Essential for Translesion DNA Synthesis in Mammalian Cells
URI	https://www.ncbi.nlm.nih.gov/pubmed/21931560 https://www.proquest.com/docview/900776235 https://pubmed.ncbi.nlm.nih.gov/PMC3169526 https://doaj.org/article/bd8b7458253a4fe6ac0abb4029cfcd8a http://dx.doi.org/10.1371/journal.pgen.1002262
Volume	7
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