Splicing component ISY1 interacts with APE1 and regulates base excision repair

Cellular genome is continuously challenged by endogenous and exogenous DNA damaging agents. In the genome, base modifications are the most common form of DNA damage. Base excision DNA repair (BER) is the most important pathway for the removal of oxidized or alkylated DNA. If these base modifications continue to persist, the replisome may stall at DNA lesions, causing the replication fork to collapse, leading to genetic instability. While the main components of the BER pathway are well defined, its regulatory mechanism remains poorly understood. We report here that apurinic/apyrimidinic endonuclease 1 (APE1), a multifunctional protein interacts with the pre-mRNA splicing factor ISY1. However, this interaction is independent of DNA or RNA based upon our pull-down experimental results. ISY1 expression is induced by oxidative or DNA alkylation damage, which would then provide an immediate up-regulation of APE1 activity in vivo and enhanced BER of oxidized bases. This was supported from our results of in vitro reconstituted experiment suggesting that ISY1 can stimulate 5’-3’ endonuclease 1 activity of APE1 in both the short- and long-patch BER pathways and increase its binding to AP site DNA. The interaction between ISY1 and APE1 also establishes a connection between DNA damage repair and pre-mRNA splicing. Based upon these results, we propose that ISY1 is an important regulator of BER and enhances the ability of APE1 to efficiently recognize abasic sites in DNA. Role of ISY1 becomes important in aging tissues where decreased APE1 activity results in the accumulation of oxidative genomic damages. Therefore, ISY1 may work as an anti-aging factor. Induction of ISY1 in malignancies could constitute a mechanism to avoid apoptotic death after treatment with alkylating agents. Citation Format: Aruna Jaiswal, Elizabeth Williamson, Bhavita Patel, Gayathri Srinivasan, Kimi Kong, Carrie Lomelino, Satya Narayan, Robert Hromas. Splicing component ISY1 interacts with APE1 and regulates base excision repair [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1758.