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The splicing component ISY1 regulates APE1 in base excision repair.

ABSTRACT: 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.

SUBMITTER: Jaiswal AS

PROVIDER: S-EPMC7185567 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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The splicing component ISY1 regulates APE1 in base excision repair.

Jaiswal Aruna S AS Williamson Elizabeth A EA Srinivasan Gayathri G Kong Kimi K Lomelino Carrie L CL McKenna Robert R Walter Christi C Sung Patrick P Narayan Satya S Hromas Robert R

DNA repair 20191213

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 ...[more]

PMID: 31887540

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Project description:Although chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of platinum drugs, the mechanisms of this toxicity remain unknown. Previous work in our laboratory suggests that cisplatin-induced CIPN is secondary to DNA damage which is susceptible to base excision repair (BER). To further examine this hypothesis, we studied the effects of cisplatin, oxaliplatin, and carboplatin on cell survival, DNA damage, ROS production, and functional endpoints in rat sensory neurons in culture in the absence or presence of reduced expression of the BER protein AP endonuclease/redox factor-1 (APE1). Using an in situ model of peptidergic sensory neuron function, we examined the effects of the platinum drugs on hind limb capsaicin-evoked vasodilatation. Exposing sensory neurons in culture to the three platinum drugs caused a concentration-dependent increase in apoptosis and cell death, although the concentrations of carboplatin were 10 fold higher than cisplatin. As previously observed with cisplatin, oxaliplatin and carboplatin also increased DNA damage as indicated by an increase in phospho-H2AX and reduced the capsaicin-evoked release of CGRP from neuronal cultures. Both cisplatin and oxaliplatin increased the production of ROS as well as 8-oxoguanine DNA adduct levels, whereas carboplatin did not. Reducing levels of APE1 in neuronal cultures augmented the cisplatin and oxaliplatin induced toxicity, but did not alter the effects of carboplatin. Using an in vivo model, systemic injection of cisplatin (3 mg/kg), oxaliplatin (3 mg/kg), or carboplatin (30 mg/kg) once a week for three weeks caused a decrease in capsaicin-evoked vasodilatation, which was delayed in onset. The effects of cisplatin on capsaicin-evoked vasodilatation were attenuated by chronic administration of E3330, a redox inhibitor of APE1 that serendipitously enhances APE1 DNA repair activity in sensory neurons. These outcomes support the importance of the BER pathway, and particularly APE1, in sensory neuropathy caused by cisplatin and oxaliplatin, but not carboplatin and suggest that augmenting DNA repair could be a therapeutic target for CIPN.

Dataset Information

The splicing component ISY1 regulates APE1 in base excision repair.

Publications

The splicing component ISY1 regulates APE1 in base excision repair.

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