TY - JOUR

T1 - Insights into Mechanisms of Damage Recognition and Catalysis by APE1-like Enzymes

AU - Bulygin, Anatoly A.

AU - Fedorova, Olga S.

AU - Kuznetsov, Nikita

N1 - Funding Information: Funding: This work was partially supported by a Russian-government-funded project (No. 121031300041-4). The part of the work involving the MD simulations was specifically funded by Russian Science Foundation, grant No. 21-14-00018. Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2022/4/1

Y1 - 2022/4/1

N2 - Apurinic/apyrimidinic (AP) endonucleases are the key DNA repair enzymes in the base excision repair (BER) pathway, and are responsible for hydrolyzing phosphodiester bonds on the 5′ side of an AP site. The enzymes can recognize not only AP sites but also some types of damaged bases, such as 1,N6-ethenoadenosine, α-adenosine, and 5,6-dihydrouridine. Here, to elucidate the mechanism underlying such a broad substrate specificity as that of AP endonucleases, we per-formed a computational study of four homologous APE1-like endonucleases: insect (Drosophila melanogaster) Rrp1, amphibian (Xenopus laevis) APE1 (xAPE1), fish (Danio rerio) APE1 (zAPE1), and human APE1 (hAPE1). The contact between the amino acid residues of the active site of each ho-mologous APE1-like enzyme and the set of damaged DNA substrates was analyzed. A comparison of molecular dynamic simulation data with the known catalytic efficiency of these enzymes al-lowed us to gain a deep insight into the differences in the efficiency of the cleavage of various damaged nucleotides. The obtained data support that the amino acid residues within the “damage recognition” loop containing residues Asn222–Ala230 significantly affect the catalytic-complex formation. Moreover, every damaged nucleotide has its unique position and a specific set of interactions with the amino acid residues of the active site.

AB - Apurinic/apyrimidinic (AP) endonucleases are the key DNA repair enzymes in the base excision repair (BER) pathway, and are responsible for hydrolyzing phosphodiester bonds on the 5′ side of an AP site. The enzymes can recognize not only AP sites but also some types of damaged bases, such as 1,N6-ethenoadenosine, α-adenosine, and 5,6-dihydrouridine. Here, to elucidate the mechanism underlying such a broad substrate specificity as that of AP endonucleases, we per-formed a computational study of four homologous APE1-like endonucleases: insect (Drosophila melanogaster) Rrp1, amphibian (Xenopus laevis) APE1 (xAPE1), fish (Danio rerio) APE1 (zAPE1), and human APE1 (hAPE1). The contact between the amino acid residues of the active site of each ho-mologous APE1-like enzyme and the set of damaged DNA substrates was analyzed. A comparison of molecular dynamic simulation data with the known catalytic efficiency of these enzymes al-lowed us to gain a deep insight into the differences in the efficiency of the cleavage of various damaged nucleotides. The obtained data support that the amino acid residues within the “damage recognition” loop containing residues Asn222–Ala230 significantly affect the catalytic-complex formation. Moreover, every damaged nucleotide has its unique position and a specific set of interactions with the amino acid residues of the active site.

KW - active-site plasticity

KW - apurinic/apyrimidinic endonuclease

KW - base excision repair

KW - conformational dynamics

KW - damaged nucleotide

KW - nucleotide eversion

KW - nucleotide incision activity

KW - DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism

KW - Substrate Specificity

KW - Nucleotides/metabolism

KW - Drosophila melanogaster/genetics

KW - Animals

KW - DNA Repair

KW - Catalysis

KW - DNA Damage

KW - Nucleic Acid Conformation

KW - Amino Acids/genetics

KW - Endonucleases/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85128152618&partnerID=8YFLogxK

U2 - 10.3390/ijms23084361

DO - 10.3390/ijms23084361

M3 - Article

C2 - 35457179

AN - SCOPUS:85128152618

VL - 23

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 8

M1 - 4361

ER -