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Article

TENT4A Non-Canonical Poly(A) Polymerase Regulates DNA-Damage Tolerance via Multiple Pathways That Are Mutated in Endometrial Cancer

1
Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel
2
The Mantoux Bioinformatics Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot 7610001, Israel
3
Bioinformatics Unit, Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot 7610001, Israel
4
Center for Integrated Protein Science at the Department of Chemistry, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, 81377 München, Germany
5
Chemistry Department, New York University, New York, NY 10003, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Alfonso Baldi
Int. J. Mol. Sci. 2021, 22(13), 6957; https://doi.org/10.3390/ijms22136957
Received: 25 April 2021 / Revised: 20 June 2021 / Accepted: 21 June 2021 / Published: 28 June 2021
(This article belongs to the Section Biochemistry)
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. View Full-Text
Keywords: TLS; DNA repair; poly(A) RNA polymerase; translesion; lesion bypass TLS; DNA repair; poly(A) RNA polymerase; translesion; lesion bypass
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MDPI and ACS Style

Swain, U.; Friedlander, G.; Sehrawat, U.; Sarusi-Portuguez, A.; Rotkopf, R.; Ebert, C.; Paz-Elizur, T.; Dikstein, R.; Carell, T.; Geacintov, N.E.; Livneh, Z. TENT4A Non-Canonical Poly(A) Polymerase Regulates DNA-Damage Tolerance via Multiple Pathways That Are Mutated in Endometrial Cancer. Int. J. Mol. Sci. 2021, 22, 6957. https://doi.org/10.3390/ijms22136957

AMA Style

Swain U, Friedlander G, Sehrawat U, Sarusi-Portuguez A, Rotkopf R, Ebert C, Paz-Elizur T, Dikstein R, Carell T, Geacintov NE, Livneh Z. TENT4A Non-Canonical Poly(A) Polymerase Regulates DNA-Damage Tolerance via Multiple Pathways That Are Mutated in Endometrial Cancer. International Journal of Molecular Sciences. 2021; 22(13):6957. https://doi.org/10.3390/ijms22136957

Chicago/Turabian Style

Swain, Umakanta, Gilgi Friedlander, Urmila Sehrawat, Avital Sarusi-Portuguez, Ron Rotkopf, Charlotte Ebert, Tamar Paz-Elizur, Rivka Dikstein, Thomas Carell, Nicholas E. Geacintov, and Zvi Livneh. 2021. "TENT4A Non-Canonical Poly(A) Polymerase Regulates DNA-Damage Tolerance via Multiple Pathways That Are Mutated in Endometrial Cancer" International Journal of Molecular Sciences 22, no. 13: 6957. https://doi.org/10.3390/ijms22136957

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