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Nucleic Acids Research Advance Access published online on April 28, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp275
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© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Nucleic Acid Enzymes

Identification of Apurinic/apyrimidinic endonuclease 1 (APE1) as the endoribonuclease that cleaves c-myc mRNA

Tavish Barnes1, Wan-Cheol Kim1, Anil K. Mantha2, Sang-Eun Kim1, Tadahide Izumi3, Sankar Mitra2 and Chow H. Lee1,*

1Chemistry Program, University of Northern British Columbia, 3333 University Way, Prince George, British Columbia V2N 4Z9, Canada, 2Sealy Center for Molecular Medicine and Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555 and 3Health Sciences Center, Louisiana State University, New Orleans, LA 70112, USA

*To whom correspondence should be addressed. Tel: +1 250 960 5413; Fax: +1 250 960 5170; Email: leec{at}unbc.ca.

Received March 5, 2009. Revised April 1, 2009. Accepted April 13, 2009.

Endonucleolytic cleavage of the coding region determinant (CRD) of c-myc mRNA appears to play a critical role in regulating c-myc mRNA turnover. Using 32P-labeled c-myc CRD RNA as substrate, we have purified and identified two endoribonucleases from rat liver polysomes that are capable of cleaving the transcript in vitro. A 17-kDa enzyme was identified as RNase1. Apurinic/apyrimidinic (AP) DNA endonuclease 1 (APE1) was identified as the 35-kDa endoribonuclease that preferentially cleaves in between UA and CA dinucleotides of c-myc CRD RNA. APE1 was further confirmed to be the 35-kDa endoribonuclease because: (i) the endoribonuclease activity of the purified 35-kDa native enzyme was specifically immuno-depleted with APE1 monoclonal antibody, and (ii) recombinant human APE1 generated identical RNA cleavage patterns as the native liver enzyme. Studies using E96A and H309N mutants of APE1 suggest that the endoribonuclease activity for c-myc CRD RNA shares the same active center with the AP-DNA endonuclease activity. Transient knockdown of APE1 in HeLa cells led to increased steady-state level of c-myc mRNA and its half-life. We conclude that the ability to cleave RNA dinucleotides is a previously unidentified function of APE1 and it can regulate c-myc mRNA level possibly via its endoribonuclease activity.


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