Stephanie Biber, Helmut Pospiech, Vanesa Gottifredi, Lisa Wiesmüller, Multiple biochemical properties of the p53 molecule contribute to activation of polymerase iota-dependent DNA damage tolerance, Nucleic Acids Research, Volume 48, Issue 21, 2 December 2020, Pages 12188–12203, https://doi.org/10.1093/nar/gkaa974
Multiple biochemical properties of the p53 molecule contribute to activation of polymerase iota-dependent DNA damage tolerance
|Author:||Biber, Stephanie1; Pospiech, Helmut2,3; Gottifredi, Vanesa4;|
1Department of Obstetrics and Gynecology, Ulm University, Ulm 89075, Germany
2Project group Biochemistry, Leibniz Institute on Aging – Fritz Lipmann Institute, D-07745 Jena, Germany
3Faculty of Biochemistry and Molecular Medicine, FIN-90014 University of Oulu, Finland
4Cell Cycle and Genomic Stability Laboratory, Fundaci´on Instituto Leloir, Buenos Aires C1405BWE, Argentina
|Online Access:||PDF Full Text (PDF, 5.6 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe202103016149
Oxford University Press,
|Publish Date:|| 2021-03-01
We have previously reported that p53 decelerates nascent DNA elongation in complex with the translesion synthesis (TLS) polymerase ι (POLι) which triggers a homology-directed DNA damage tolerance (DDT) pathway to bypass obstacles during DNA replication. Here, we demonstrate that this DDT pathway relies on multiple p53 activities, which can be disrupted by TP53 mutations including those frequently found in cancer tissues. We show that the p53-mediated DDT pathway depends on its oligomerization domain (OD), while its regulatory C-terminus is not involved. Mutation of residues S315 and D48/D49, which abrogate p53 interactions with the DNA repair and replication proteins topoisomerase I and RPA, respectively, and residues L22/W23, which disrupt formation of p53-POLι complexes, all prevent this DDT pathway. Our results demonstrate that the p53-mediated DDT requires the formation of a DNA binding-proficient p53 tetramer, recruitment of such tetramer to RPA-coated forks and p53 complex formation with POLι. Importantly, our mutational analysis demonstrates that transcriptional transactivation is dispensable for the POLι-mediated DDT pathway, which we show protects against DNA replication damage from endogenous and exogenous sources.
Nucleic acids research
|Pages:||12188 - 12203|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
German Cancer Aid, Priority Program ‘Translational Oncology’ ; Deutsche Forschungsgemeinschaft (DFG, Research Training Group) [2544 to L.W.]; German Research Foundation (DFG) Graduate School of Molecular Medicine, Ulm University (PhD fellowship to S.B.) as well as the Start-up Funding Program of the Medical Faculty of Ulm University (‘Bausteinprogramm’) [L.SBN.0160 to S.B.]; V.G. was supported by the Alexander von Humboldt Foundation during her extended stay in the Wiesmüller laboratory (Georg Forster Award to V.G.). Funding for open access charge: DFG and German Cancer Aid.
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.
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