Phosphorylation Alters the Properties of Pol η: Implications for Translesion Synthesis
Summary: There are significant ambiguities regarding how DNA polymerase η is recruited to DNA lesion sites in stressed cells while avoiding normal replication forks in non-stressed cells. Even less is known about the mechanisms responsible for Pol η-induced mutations in cancer genomes. We show that...
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| Format: | Article |
| Language: | English |
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Elsevier
2018-08-01
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| Series: | iScience |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S258900421830097X |
| _version_ | 1818339928955682816 |
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| author | Chandana Peddu Sufang Zhang Hong Zhao Agnes Wong Ernest Y.C. Lee Marietta Y.W.T. Lee Zhongtao Zhang |
| author_facet | Chandana Peddu Sufang Zhang Hong Zhao Agnes Wong Ernest Y.C. Lee Marietta Y.W.T. Lee Zhongtao Zhang |
| author_sort | Chandana Peddu |
| collection | DOAJ |
| description | Summary: There are significant ambiguities regarding how DNA polymerase η is recruited to DNA lesion sites in stressed cells while avoiding normal replication forks in non-stressed cells. Even less is known about the mechanisms responsible for Pol η-induced mutations in cancer genomes. We show that there are two safeguards to prevent Pol η from adventitious participation in normal DNA replication. These include sequestration by a partner protein and low basal activity. Upon cellular UV irradiation, phosphorylation enables Pol η to be released from sequestration by PDIP38 and activates its polymerase function through increased affinity toward monoubiquitinated proliferating cell nuclear antigen (Ub-PCNA). Moreover, the high-affinity binding of phosphorylated Pol η to Ub-PCNA limits its subsequent displacement by Pol δ. Consequently, activated Pol η replicates DNA beyond the lesion site and potentially introduces clusters of mutations due to its low fidelity. This mechanism could account for the prevalence of Pol η signatures in cancer genome. : Biochemistry; Molecular Biology; Molecular Genetics Subject Areas: Biochemistry, Molecular Biology, Molecular Genetics |
| first_indexed | 2024-12-13T15:34:48Z |
| format | Article |
| id | doaj.art-5fcae8b5cbeb4c4aaf5ed0fb623cf3e3 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-13T15:34:48Z |
| publishDate | 2018-08-01 |
| publisher | Elsevier |
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| series | iScience |
| spelling | doaj.art-5fcae8b5cbeb4c4aaf5ed0fb623cf3e32022-12-21T23:40:04ZengElsevieriScience2589-00422018-08-0165267Phosphorylation Alters the Properties of Pol η: Implications for Translesion SynthesisChandana Peddu0Sufang Zhang1Hong Zhao2Agnes Wong3Ernest Y.C. Lee4Marietta Y.W.T. Lee5Zhongtao Zhang6Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USADepartment of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USADepartment of Pathology, New York Medical College, Valhalla, NY 10595, USADepartment of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USADepartment of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USADepartment of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USADepartment of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA; Corresponding authorSummary: There are significant ambiguities regarding how DNA polymerase η is recruited to DNA lesion sites in stressed cells while avoiding normal replication forks in non-stressed cells. Even less is known about the mechanisms responsible for Pol η-induced mutations in cancer genomes. We show that there are two safeguards to prevent Pol η from adventitious participation in normal DNA replication. These include sequestration by a partner protein and low basal activity. Upon cellular UV irradiation, phosphorylation enables Pol η to be released from sequestration by PDIP38 and activates its polymerase function through increased affinity toward monoubiquitinated proliferating cell nuclear antigen (Ub-PCNA). Moreover, the high-affinity binding of phosphorylated Pol η to Ub-PCNA limits its subsequent displacement by Pol δ. Consequently, activated Pol η replicates DNA beyond the lesion site and potentially introduces clusters of mutations due to its low fidelity. This mechanism could account for the prevalence of Pol η signatures in cancer genome. : Biochemistry; Molecular Biology; Molecular Genetics Subject Areas: Biochemistry, Molecular Biology, Molecular Geneticshttp://www.sciencedirect.com/science/article/pii/S258900421830097X |
| spellingShingle | Chandana Peddu Sufang Zhang Hong Zhao Agnes Wong Ernest Y.C. Lee Marietta Y.W.T. Lee Zhongtao Zhang Phosphorylation Alters the Properties of Pol η: Implications for Translesion Synthesis iScience |
| title | Phosphorylation Alters the Properties of Pol η: Implications for Translesion Synthesis |
| title_full | Phosphorylation Alters the Properties of Pol η: Implications for Translesion Synthesis |
| title_fullStr | Phosphorylation Alters the Properties of Pol η: Implications for Translesion Synthesis |
| title_full_unstemmed | Phosphorylation Alters the Properties of Pol η: Implications for Translesion Synthesis |
| title_short | Phosphorylation Alters the Properties of Pol η: Implications for Translesion Synthesis |
| title_sort | phosphorylation alters the properties of pol η implications for translesion synthesis |
| url | http://www.sciencedirect.com/science/article/pii/S258900421830097X |
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