TY - JOUR

T1 - Human Tyrosyl-DNA Phosphodiesterase 1 Possesses Transphosphooligonucleotidation Activity With Primary Alcohols

AU - Dyrkheeva, Nadezhda

AU - Anarbaev, Rashid

AU - Lebedeva, Natalia

AU - Kuprushkin, Maxim

AU - Kuznetsova, Alexandra

AU - Kuznetsov, Nikita

AU - Rechkunova, Nadejda

AU - Lavrik, Olga

N1 - Publisher Copyright: © Copyright © 2020 Dyrkheeva, Anarbaev, Lebedeva, Kuprushkin, Kuznetsova, Kuznetsov, Rechkunova and Lavrik. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2020/12/23

Y1 - 2020/12/23

N2 - Human tyrosyl-DNA phosphodiesterase 1 (TDP1) belongs to the phospholipase D superfamily, whose members contain paired catalytic histidine and lysine residues within two conserved motifs and hydrolyze phosphodiester bonds. TDP1 is a DNA repair enzyme that processes 3′ DNA end blocking lesions and a wide range of synthetic DNA adducts as a substrate. TDP1 hydrolyzes DNA-adducts via two coordinated SN2 nucleophilic attacks mediated by the action of two histidine residues and leads to the formation of the covalent intermediate. Hydrolysis of this intermediate is proposed to be carried out by a water molecule that is activated by the His493 residue acting as a general base. It was known that phospholipase D enzymes are able to catalyze not only hydrolysis but also a transphosphatidylation reaction in the presence of primary alcohols in which they transfer the substrate to the alcohol instead of water. Here, we first demonstrated that TDP1 is able to undergo a “transphosphooligonucleotidation” reaction, transferring the substrate residue to the alcohol, thus inducing the formation of covalent DNA adducts with different primary alcohol residues. Such adducts can be accumulated in the conditions of high concentration of alcohol. We demonstrated that glycerol residue was efficiently cleaved from the 3′-end by TDP1 but not by its mutant form associated with the disease spinocerebellar ataxia with axonal neuropathy. Therefore, the second reaction step can be carried out not only by a water molecule but also by the other small nucleophilic molecules, e.g., glycerol and ethanol. Thus, in some cases, TDP1 can be regarded not only as a repair enzyme but also as a source of DNA damage especially in the case of mutation. Such damages can make a negative contribution to the stability of cell vitality.

AB - Human tyrosyl-DNA phosphodiesterase 1 (TDP1) belongs to the phospholipase D superfamily, whose members contain paired catalytic histidine and lysine residues within two conserved motifs and hydrolyze phosphodiester bonds. TDP1 is a DNA repair enzyme that processes 3′ DNA end blocking lesions and a wide range of synthetic DNA adducts as a substrate. TDP1 hydrolyzes DNA-adducts via two coordinated SN2 nucleophilic attacks mediated by the action of two histidine residues and leads to the formation of the covalent intermediate. Hydrolysis of this intermediate is proposed to be carried out by a water molecule that is activated by the His493 residue acting as a general base. It was known that phospholipase D enzymes are able to catalyze not only hydrolysis but also a transphosphatidylation reaction in the presence of primary alcohols in which they transfer the substrate to the alcohol instead of water. Here, we first demonstrated that TDP1 is able to undergo a “transphosphooligonucleotidation” reaction, transferring the substrate residue to the alcohol, thus inducing the formation of covalent DNA adducts with different primary alcohol residues. Such adducts can be accumulated in the conditions of high concentration of alcohol. We demonstrated that glycerol residue was efficiently cleaved from the 3′-end by TDP1 but not by its mutant form associated with the disease spinocerebellar ataxia with axonal neuropathy. Therefore, the second reaction step can be carried out not only by a water molecule but also by the other small nucleophilic molecules, e.g., glycerol and ethanol. Thus, in some cases, TDP1 can be regarded not only as a repair enzyme but also as a source of DNA damage especially in the case of mutation. Such damages can make a negative contribution to the stability of cell vitality.

KW - 3′-phosphoglycolate

KW - alcohol

KW - DNA damage

KW - DNA repair

KW - ethanol

KW - glycerol

KW - spinocerebellar ataxia with axonal neuropathy type 1

KW - tyrosyl-DNA phosphodiesterase 1

KW - SITE

KW - PHOSPHOLIPASE-D

KW - CRYSTAL-STRUCTURE

KW - HYDROLYSIS

KW - REPAIR

KW - ENZYME

KW - SPINOCEREBELLAR ATAXIA

KW - ANTICANCER

KW - TDP1

KW - PHOSPHATIDYLCHOLINE

KW - tyrosyl-DNA phosphodiesterase 1, 3 '-phosphoglycolate

UR - http://www.scopus.com/inward/record.url?scp=85099156810&partnerID=8YFLogxK

U2 - 10.3389/fcell.2020.604732

DO - 10.3389/fcell.2020.604732

M3 - Article

C2 - 33425909

AN - SCOPUS:85099156810

VL - 8

JO - Frontiers in Cell and Developmental Biology

JF - Frontiers in Cell and Developmental Biology

SN - 2296-634X

M1 - 604732

ER -