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Journal article
TENT4A Non-Canonical Poly(A) Polymerase Regulates DNA-Damage Tolerance via Multiple Pathways That Are Mutated in Endometrial Cancer
International journal of molecular sciences, Vol.22(13), 6957
01/Jul/2021
PMID: 34203408
Abstract
TENT4A (PAPD7) is a non-canonical poly(A) polymerase, of which little is known. Here, we show that TENT4A regulates multiple biological pathways and focuses on its multilayer regulation of translesion DNA synthesis (TLS), in which error-prone DNA polymerases bypass unrepaired DNA lesions. We show that TENT4A regulates mRNA stability and/or translation of DNA polymerase η and RAD18 E3 ligase, which guides the polymerase to replication stalling sites and monoubiquitinates PCNA, thereby enabling recruitment of error-prone DNA polymerases to damaged DNA sites. Remarkably, in addition to the effect on RAD18 mRNA stability via controlling its poly(A) tail, TENT4A indirectly regulates RAD18 via the tumor suppressor CYLD and via the long non-coding antisense RNA PAXIP1-AS2, which had no known function. Knocking down the expression of TENT4A or CYLD, or overexpression of PAXIP1-AS2 led each to reduced amounts of the RAD18 protein and DNA polymerase η, leading to reduced TLS, highlighting PAXIP1-AS2 as a new TLS regulator. Bioinformatics analysis revealed that TLS error-prone DNA polymerase genes and their TENT4A-related regulators are frequently mutated in endometrial cancer genomes, suggesting that TLS is dysregulated in this cancer.
Details
- Title
- TENT4A Non-Canonical Poly(A) Polymerase Regulates DNA-Damage Tolerance via Multiple Pathways That Are Mutated in Endometrial Cancer
- Creators
- Umakanta Swain - 972WIS_INST___112Gilgi Friedlander - 972WIS_INST___890Urmila Sehrawat - 972WIS_INST___112Avital Sarusi-Portuguez - 972WIS_INST___890Ron Rotkopf - 972WIS_INST___113Charlotte Ebert - Ludwig-Maximilians-Universität MünchenTamar Paz-Elizur - 972WIS_INST___112Rivka Dikstein - 972WIS_INST___112Thomas Carell - Ludwig-Maximilians-Universität MünchenNicholas E Geacintov - New York UniversityZvi Livneh (Corresponding Author) - 972WIS_INST___112
- Resource Type
- Journal article
- Publication Details
- International journal of molecular sciences, Vol.22(13), 6957; 01/Jul/2021
- Number of pages
- 24
- Publisher
- MDPI
- Language
- English
- DOI
- https://doi.org/10.3390/ijms22136957
- PMID
- 34203408
- Grant note
- This research was funded by the Flight Attendant Medical Research Institute, Florida, USA (FAMRI #032001 to Z.L. and T.P.E.); the Israel Science Foundation (#684/12 to Z.L.), and the Minerva Foundation (#120855) with funding from the Federal German Ministry for Education and Research (to Z.L.). Funding for open access charge: Flight Attendant Medical Research Institute, Florida, USA. Z.L. is the incumbent of the Maxwell Ellis Chair for Biomedical Research. R.D. is the incumbent of the Ruth and Leonard Simon Professorial Chair of Cancer Research. G.F. is the Incumbent of the David and Stacey Cynamon Research fellow Chair in Genetics and Personalized Medicine. Author Contributions U.S. (Umakanta Swain) designed, performed, and analyzed most experiments and participated in writing the manuscript. G.F. performed the RNAseq analysis and commented on the manuscript. U.S. (Urmila Sehrawat) performed polysome profiling experiments, analyzed their data and commented on the manuscript. A.S.-P. and R.R. performed the mutational analysis based on the TCGA database. C.E., T.C. and N.E.G. provided oligonucleotides and commented on the manuscript. T.P.-E., participated in designing the experiments, analysis of the data, and writing the manuscript. R.D. provided advice, contributed to the analysis of the results, and commented on the manuscript. Z.L. conceived, devised, and supervised the study and wrote the manuscript. All authors have read and agreed to the published version of the manuscript.
- Record Identifier
- 993285951003596
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