TY - JOUR
T1 - The splicing component ISY1 regulates APE1 in base excision repair
AU - Jaiswal, Aruna S.
AU - Williamson, Elizabeth A.
AU - Srinivasan, Gayathri
AU - Kong, Kimi
AU - Lomelino, Carrie L.
AU - McKenna, Robert
AU - Walter, Christi
AU - Sung, Patrick
AU - Narayan, Satya
AU - Hromas, Robert
N1 - Funding Information:
This study was supported by grants from the National Institutes of Health (NIH) R01 CA139429 and R01 GMs109645 to RH, and R01 CA220123 to PS.
Publisher Copyright:
© 2019 The Authors
PY - 2020/2
Y1 - 2020/2
N2 - 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.
AB - 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.
KW - AP Endonuclease-1
KW - Base excision repair
KW - ISY1
KW - Oxidative stress
KW - RNA splicing
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U2 - 10.1016/j.dnarep.2019.102769
DO - 10.1016/j.dnarep.2019.102769
M3 - Article
C2 - 31887540
AN - SCOPUS:85076916714
VL - 86
JO - DNA Repair
JF - DNA Repair
SN - 1568-7864
M1 - 102769
ER -