The splicing component ISY1 regulates APE1 in base excision repair.

Autor: Jaiswal AS; Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229 United States. Electronic address: jaiswala@uthscsa.edu., Williamson EA; Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229 United States., Srinivasan G; Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229 United States., Kong K; Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229 United States., Lomelino CL; Department of Biochemistry and Molecular Biology, University of Florida Health, Gainesville, FL 32610 United States., McKenna R; Department of Biochemistry and Molecular Biology, University of Florida Health, Gainesville, FL 32610 United States., Walter C; Department of Cell Systems and Anatomy, University of Texas Health Science Center, San Antonio, TX 78229 United States., Sung P; Department of Biochemistry and Structural Biology, University of Texas Health Science Center Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT 06520 San Antonio, TX 78229 United States., Narayan S; Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL 32610 United States., Hromas R; Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229 United States. Electronic address: hromas@uthscsa.edu.
Jazyk: angličtina
Zdroj: DNA repair [DNA Repair (Amst)] 2020 Feb; Vol. 86, pp. 102769. Date of Electronic Publication: 2019 Dec 13.
DOI: 10.1016/j.dnarep.2019.102769
Abstrakt: The integrity of cellular genome is continuously challenged by endogenous and exogenous DNA damaging agents. If DNA damage is not removed in a timely fashion the replisome may stall at DNA lesions, causing fork collapse and genetic instability. Base excision DNA repair (BER) is the most important pathway for the removal of oxidized or mono-alkylated DNA. While the main components of the BER pathway are well defined, its regulatory mechanism is not yet understood. We report here that the splicing factor ISY1 enhances apurinic/apyrimidinic endonuclease 1 (APE1) activity, the multifunctional enzyme in BER, by promoting its 5'-3' endonuclease activity. ISY1 expression is induced by oxidative damage, which would provide an immediate up-regulation of APE1 activity in vivo and enhance BER of oxidized bases. We further found that APE1 and ISY1 interact, and ISY1 enhances the ability of APE1 to recognize abasic sites in DNA. Using purified recombinant proteins, we reconstituted BER and demonstrated that ISY1 markedly promoted APE1 activity in both the short- and long-patch BER pathways. Our study identified ISY1 as a regulator of the BER pathway, which would be of physiological relevance where suboptimal levels of APE1 are present. The interaction of ISY1 and APE1 also establishes a connection between DNA damage repair and pre-mRNA splicing.
(Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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