From Proteopedia

Revision as of 03:51, 30 March 2010

APURINIC/APYRIMIDINIC ENDONUCLEASE-1 (APE1)

INTRODUCTION

DNA is damaged frequently in living cells via endogenous and exogenous factors that have the ability to cause abasic sites in the DNA strand. Abasic DNA must be repaired both accuratly and efficiently in order to prevent the death of the cell or the accumulation of mutations within the genome. Abasic DNA is repaired in the base excision repair pathway. Apurinic/apyrimidinic endonuclease-1 (APE1) is the major repair enzyme in the base excision repair pathway in humans ^[1]. APE1 has the ability to cleave the phophodiester bond at the 5' end of abasic sites in damaged DNA strands ^[2]. An important point of gene regulation within a cell is the regulation of the half life of mRNA transcripts. The regulation of mRNA transcripts will control the amount of protein translated in a cell. Many mRNA transcripts have been linked to diseases such as cancer. These deleterious mRNA transcripts are known as proto-oncogene products and can greatly effect the health of cells^[3]. APE1 has also been shown to have the ability to regulate the half life of c-myc mRNA by endonucleolytically cleaving the coding region determinant (CRD) of c-myc mRNA^[4].

STRUCTURE AND FUNCTION

APE1 works in the base excision repair pathway

Damage to DNA strands within living systems is inevitable. Whether the DNA is damage due to exogenous or endogenous stimuli, the DNA must be repaired in an extremely efficient and accurate way to prevent detrimental consequences to the organism. Apurinic/apyrimidinic (AP) or abasic sites are formed within DNA strands as a result of exposure to mutangenic stimulus such as UV light or a chemical agent ^[5]. Humans have evolved in a way that we have developed different DNA repair mechanisms that are responsible for repairing the many mutations or mistakes made during the life of a cell. Enzymes within the cell perform many functions that include both acting as a catalyst in many biological processes and repairing damaged DNA. Oxidatative DNA damage can occur within a cell at rates of 1.5x105residues*cell-1*day-1, so enzymes within the cell must be able to repair the DNA ^[6]. The endonuclease APE1 repairs oxidatively damaged DNA, making APE1 essential for survival ^[7]. The presence of spontaneous hydrolytic decay and oxygen free radicals within a cell damages DNA strands which must be repaired due to the cytotoxicity of these AP sites (Fung 2005). The AP endonuclease APE1 is able to repair these AP sites in humans and APE1 seems to be the main, essential endonuclease responsible for this type of repair (Fung 2005). APE1s role in regulating the redox states of many transcription factors allows for a higher DNA-transcription factor binding affinity ^[8]. APE1 contributes to this binding affinity by reducing the AP-1 transcription factors at redox sensitive cysteine residues ^[9].

Substrate Binding

The nuclease domain

The redox domain

APE1 has been established as a vital redox enzyme that plays pivotal roles in repairing both damaged DNA and reducing transcription factors to promote higher binding affinity with DNA. Although the central dogma for mRNA decay currently favours the 3’ to 5’ deadenylation-dependent and the 5’ to 3’ decapping decay pathways, endonucleolytic cleavage intermediates have been shown to be involved in the decay of a number of mRNA (Barnes 2009). Many mRNAs, such as c-myc mRNA, have been shown to be degraded by 3’-5’ exonucleolytic activity via exonucleases (Barnes 2009). In the paper Identification of Apurinic/apyrimidinic endoribonuclease 1 (APE1) as the endoribonuclease that cleaves c-myc mRNA in vitro, Barnes et al. show that the endonuclease APE1/Ref1 is responsible for the endonucleolytic cleavage of c-myc mRNA in vitro. The vital role of APE1 now includes endonucleolytic cleavage of c-myc mRNA along with its role in redox repair of damaged DNA bases.

POPULATION VARIENTS

APE1 HAS BEEN SHOWN TO CLEAVE C-MYC MRNA

REFERENCES

1. ↑ Masood, Z.H. 2000. Functional characterization of APE1 varients identified in the human population. Nucleic Acid Research 28: 3871-3879.
2. ↑ Masood, Z.H. 2000. Functional characterization of APE1 varients identified in the human population. Nucleic Acid Research 28: 3871-3879.
3. ↑ Barnes, T., et al. 2009. Identification of Apurinic/apyrimidinic endoribonuclease 1 (APE1) as the endoribonuclease that cleaves c-myc mRNA in vitro. Nucleic Acid Research 37: 3946-3958.
4. ↑ Barnes, T., et al. 2009. Identification of Apurinic/apyrimidinic endoribonuclease 1 (APE1) as the endoribonuclease that cleaves c-myc mRNA in vitro. Nucleic Acid Research 37: 3946-3958.
5. ↑ Beloglazova, N., et al. 2004. Thermodynamic, kinetic and structural basis for recognition and repair of abasic sites in DNA by apurinic/apyrimidinic endonuclease from human placenta. Nucleic Acid Research. 32(17): 5134-5146.
6. ↑ Izumi, T. et al. 2005. Two essential but distinct functions of the mammalian abasic endonuclease. PNAS 102: 5739-5743.
7. ↑ Izumi, T. et al. 2005. Two essential but distinct functions of the mammalian abasic endonuclease. PNAS 102: 5739-5743.
8. ↑ Ando, K. et al. 2008. A new APE1/Ref-1-dependent pathway leading to reduction of NF- B and AP-1, and activation of their DNA-binding activity. Nucleic Acids Research 36: 4327-4336.
9. ↑ Ando, K. et al. 2008. A new APE1/Ref-1-dependent pathway leading to reduction of NF- B and AP-1, and activation of their DNA-binding activity. Nucleic Acids Research 36: 4327-4336.