TY - JOUR

T1 - Reading Targeted DNA Damage in the Active Demethylation Pathway: Role of Accessory Domains of Eukaryotic AP Endonucleases and Thymine-DNA Glycosylases

AU - Popov, Alexander V.

AU - Grin, Inga R.

AU - Dvornikova, Antonina P.

AU - Matkarimov, Bakhyt T.

AU - Groisman, Regina

AU - Saparbaev, Murat

AU - Zharkov, Dmitry O.

N1 - Publisher Copyright: © 2019 Elsevier Ltd

PY - 2020/3/13

Y1 - 2020/3/13

N2 - Base excision DNA repair (BER) is an important process used by all living organisms to remove nonbulky lesions from DNA. BER is usually initiated by DNA glycosylases that excise a damaged base leaving an apurinic/apyrimidinic (AP) site, and an AP endonuclease then cuts DNA at the AP site, and the repair is completed by correct nucleotide insertion, end processing, and nick ligation. It has emerged recently that the BER machinery, in addition to genome protection, is crucial for active epigenetic demethylation in the vertebrates. This pathway is initiated by TET dioxygenases that oxidize the regulatory 5-methylcytosine, and the oxidation products are treated as substrates for BER. T:G mismatch-specific thymine-DNA glycosylase (TDG) and AP endonuclease 1 (APE1) catalyze the first two steps in BER-dependent active demethylation. In addition to the well-structured catalytic domains, these enzymes possess long tails that are structurally uncharacterized but involved in multiple interactions and regulatory functions. In this review, we describe the known roles of the tails in TDG and APE1, discuss the importance of order and disorder in their structure, and consider the evolutionary aspects of these accessory protein regions. We also propose that the tails may be important for the enzymes’ oligomerization on DNA, an aspect of their function that only recently gained attention.

AB - Base excision DNA repair (BER) is an important process used by all living organisms to remove nonbulky lesions from DNA. BER is usually initiated by DNA glycosylases that excise a damaged base leaving an apurinic/apyrimidinic (AP) site, and an AP endonuclease then cuts DNA at the AP site, and the repair is completed by correct nucleotide insertion, end processing, and nick ligation. It has emerged recently that the BER machinery, in addition to genome protection, is crucial for active epigenetic demethylation in the vertebrates. This pathway is initiated by TET dioxygenases that oxidize the regulatory 5-methylcytosine, and the oxidation products are treated as substrates for BER. T:G mismatch-specific thymine-DNA glycosylase (TDG) and AP endonuclease 1 (APE1) catalyze the first two steps in BER-dependent active demethylation. In addition to the well-structured catalytic domains, these enzymes possess long tails that are structurally uncharacterized but involved in multiple interactions and regulatory functions. In this review, we describe the known roles of the tails in TDG and APE1, discuss the importance of order and disorder in their structure, and consider the evolutionary aspects of these accessory protein regions. We also propose that the tails may be important for the enzymes’ oligomerization on DNA, an aspect of their function that only recently gained attention.

KW - AP endonucleases

KW - DNA glycosylases

KW - DNA repair

KW - protein domains

KW - structural disorder

UR - http://www.scopus.com/inward/record.url?scp=85077021990&partnerID=8YFLogxK

U2 - 10.1016/j.jmb.2019.12.020

DO - 10.1016/j.jmb.2019.12.020

M3 - Review article

C2 - 31866293

AN - SCOPUS:85077021990

VL - 432

SP - 1747

EP - 1768

JO - Journal of Molecular Biology

JF - Journal of Molecular Biology

SN - 0022-2836

IS - 6

ER -