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Tyrosyl-DNA phosphodiesterase 1 (TDP1) and SPRTN protease repair histone 3 and topoisomerase 1 DNA-protein crosslinks in vivo

Antičević, Ivan; Otten, Cecile; Vinković, Luka; Jukić, Luka; Popović, Marta (2023) Tyrosyl-DNA phosphodiesterase 1 (TDP1) and SPRTN protease repair histone 3 and topoisomerase 1 DNA-protein crosslinks in vivo. Open Biology, 13 . ISSN 2046-2441

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DNA–protein crosslinks (DPCs) are frequent and damaging DNA lesions that affect all DNA transactions, which in turn can lead to the formation of double-strand breaks, genomic instability and cell death. At the organismal level, impaired DPC repair (DPCR) is associated with cancer, ageing and neurodegeneration. Despite the severe consequences of DPCs, little is known about theprocesses underlying repair pathways at the organism level. SPRTN is a protease that removes most cellular DPCs during replication, whereas tyrosyl-DNA phosphodiesterase 1 repairs one of the most abundant enzymatic DPCs, topoisomerase 1-DPC (TOP1-DPC). How these two enzymes repair DPCs at the organism level is currently unknown. We perform phylogenetic, syntenic, structural and expression analysis to compare tyrosyl-DNA phosphodiesterase 1 (TDP1) orthologues between human, mouse and zebrafish. Using the zebrafish animal model and human cells, we demonstrate that TDP1 and SPRTN repair endogenous, camptothecinand formaldehyde-induced DPCs, including histone H3- and TOP1-DPCs. We show that resolution of H3-DNA crosslinks depends on upstream proteolysis by SPRTN and subsequent peptide removal by TDP1 in RPE1 cells and zebrafish embryos, whereas SPRTN and TDP1 function in different pathways in the repair of endogenous TOP1-DPCs and total DPCs. Furthermore, we have found increased TDP2 expression in TDP1-deficient cells and embryos. Understanding the role of TDP1 in DPCR at the cellular and organismal levels could provide an impetus for the development of new drugs and combination therapies with TOP1-DPC inducing drugs.

Item Type: Article
Uncontrolled Keywords: DNA repair, DNA–protein crosslinks, tyrosylDNA phosphodiesterase 1, SPRTN, zebrafish, histones
Subjects: NATURAL SCIENCES > Biology > Biochemistry and Molecular Biology
NATURAL SCIENCES > Biology > General Biology
Divisions: Division for Marine and Enviromental Research
Project titleProject leaderProject codeProject type
Razumijevanje popravka unakrsnog vezanja DNA-Protein in vivo koristeći zebricu kao istraživački model-DNAPROMarta PopovićUIP-2017-05-5258HRZZ
Depositing User: Marta Popović
Date Deposited: 24 Oct 2023 07:58
DOI: 10.1098/rsob.230113

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