Homo sapiens L. (human) [HSA]

FULL NAME: DNA-(apurinic or apyrimidinic site) lyase


DESCRIPTION:
Multifunctional protein that plays a central role in the cellular response to oxidative stress. The two major activities of APEX1 in DNA repair and redox regulation of transcriptional factors. Functions as a apurinic/apyrimidinic (AP) endodeoxyribonuclease in the DNA base excision repair (BER) pathway of DNA lesions induced by oxidative and alkylating agents. Initiates repair of AP sites in DNA by catalyzing hydrolytic incision of the phosphodiester backbone immediately adjacent to the damage, generating a single-strand break with 5'-deoxyribose phosphate and 3'-hydroxyl ends. Does also incise at AP sites in the DNA strand of DNA/RNA hybrids, single-stranded DNA regions of R-loop structures, and single-stranded RNA molecules. Has a 3'-5' exoribonuclease activity on mismatched deoxyribonucleotides at the 3' termini of nicked or gapped DNA molecules during short-patch BER. Possesses a DNA 3' phosphodiesterase activity capable of removing lesions (such as phosphoglycolate) blocking the 3' side of DNA strand breaks. May also play a role in the epigenetic regulation of gene expression by participating to DNA demethylation. Acts as a loading factor for POLB onto non-incised AP sites in DNA and stimulates the 5'-terminal deoxyribose 5'-phosphate (dRp) excision activity of POLB. Plays a role in the protection from granzymes-mediated cellular repair leading to cell death. Also involved in the DNA cleavage step of class switch recombination (CSR). On the other hand, APEX1 also exerts reversible nuclear redox activity to regulate DNA binding affinity and transcriptional activity of transcriptional factors by controlling the redox status of their DNA-binding domain, such as the FOS/JUN AP-1 complex after exposure to IR. Involved in calcium-dependent down-regulation of parathyroid hormone (PTH) expression by binding to negative calcium response elements (nCaREs). Together with HNRNPL or the dimer XRCC5/XRCC6, associates with nCaRE, acting as an activator of transcriptional repression. Stimulates the YBX1-mediated MDR1 promoter activity, when acetylated at Lys-6 and Lys-7, leading to drug resistance. Acts also as an endoribonuclease involved in the control of single-stranded RNA metabolism. Plays a role in regulating MYC mRNA turnover by preferentially cleaving in between UA and CA dinucleotides of the MYC coding region determinant (CRD). In association with NMD1, plays a role in the rRNA quality control process during cell cycle progression. Associates, together with YBX1, on the MDR1 promoter. Together with NPM1, associates with rRNA. Binds DNA and RNA.

MISCELLANEOUS:
Extract of mitochondria, but not of nuclei or cytosol, cleaves recombinant APEX1 to generate a mitochondrial APEX1-sized product (By similarity). The specific activity of the cleaved mitochondrial endodeoxyribonuclease appeared to be about 3-fold higher than that of the full-length form.


STRUCTURE SIMILARITY:
Belongs to the DNA repair enzymes AP/ExoA family.


CATALYTIC ACTIVITY:
The C-O-P bond 3' to the apurinic or apyrimidinic site in DNA is broken by a beta-elimination reaction, leaving a 3'-terminal unsaturated sugar and a product with a terminal 5'-phosphate.


ENZYME REGULATION:
NPM1 stimulates endodeoxyribonuclease activity on double-stranded DNA with AP sites, but inhibits endoribonuclease activity on single-stranded RNA containing AP sites.


POST-TRANSLATIONAL MODIFICATION:
Cleaved at Lys-31 by granzyme A to create the mitochondrial form; leading in reduction of binding to DNA, AP endodeoxynuclease activity, redox activation of transcription factors and to enhanced cell death. Cleaved by granzyme K; leading to intracellular ROS accumulation and enhanced cell death after oxidative stress.
Acetylated on Lys-6 and Lys-7. Acetylation is increased by the transcriptional coactivator EP300 acetyltransferase, genotoxic agents like H(2)O(2) and methyl methanesulfonate (MMS). Acetylation increases its binding affinity to the negative calcium response element (nCaRE) DNA promoter. The acetylated form induces a stronger binding of YBX1 to the Y-box sequence in the MDR1 promoter than the unacetylated form. Deacetylated on lysines. Lys-6 and Lys-7 are deacetylated by SIRT1.
Ubiquitinated by MDM2; leading to translocation to the cytoplasm and proteasomal degradation.
Phosphorylated. Phosphorylation by kinase PKC or casein kinase CK2 results in enhanced redox activity that stimulates binding of the FOS/JUN AP-1 complex to its cognate binding site. AP-endodeoxyribonuclease activity is not affected by CK2-mediated phosphorylation.
Cys-65 and Cys-93 are nitrosylated in response to nitric oxide (NO) and lead to the exposure of the nuclear export signal (NES).


RELATED PATHWAY(S):
base excision repair (BER)


RELATED DAMAGE:
3'-OH end
3'-P
3'-PUA termini
8-(hydroxymethyl)-εC
AP-site


Amino acids sequence

        10         20         30         40         50         60
MPKRGKKGAV AEDGDELRTE PEAKKSKTAA KKNDKEAAGE GPALYEDPPD QKTSPSGKPA
        70         80         90        100        110        120
TLKICSWNVD GLRAWIKKKG LDWVKEEAPD ILCLQETKCS ENKLPAELQE LPGLSHQYWS
       130        140        150        160        170        180
APSDKEGYSG VGLLSRQCPL KVSYGIGDEE HDQEGRVIVA EFDSFVLVTA YVPNAGRGLV
       190        200        210        220        230        240
RLEYRQRWDE AFRKFLKGLA SRKPLVLCGD LNVAHEEIDL RNPKGNKKNA GFTPQERQGF
       250        260        270        280        290        300
GELLQAVPLA DSFRHLYPNT PYAYTFWTYM MNARSKNVGW RLDYFLLSHS LLPALCDSKI
       310
RSKALGSDHC PITLYLAL    

Encoded by APEX1 gene

FULL NAME: APEX nuclease (multifunctional DNA repair enzyme) 1


OTHER NAME(S):
APE
APE1
APEN
APEX
APX
HAP1
REF1


DESCRIPTION:
Apurinic/apyrimidinic (AP) sites occur frequently in DNA molecules by spontaneous hydrolysis, by DNA damaging agents or by DNA glycosylases that remove specific abnormal bases. AP sites are pre-mutagenic lesions that can prevent normal DNA replication so the cell contains systems to identify and repair such sites. Class II AP endonucleases cleave the phosphodiester backbone 5' to the AP site. This gene encodes the major AP endonuclease in human cells. Splice variants have been found for this gene; all encode the same protein. [provided by RefSeq, Jul 2008]


Nucleic acid sequence

        10         20         30         40         50         60
atgccgaagc gtgggaaaaa gggagcggtg gcggaagacg gggatgagct caggacagag
        70         80         90        100        110        120
ccagaggcca agaagagtaa gacggccgca aagaaaaatg acaaagaggc agcaggagag
       130        140        150        160        170        180
ggcccagccc tgtatgagga ccccccagat cagaaaacct cacccagtgg caaacctgcc
       190        200        210        220        230        240
acactcaaga tctgctcttg gaatgtggat gggcttcgag cctggattaa gaagaaagga
       250        260        270        280        290        300
ttagattggg taaaggaaga agccccagat atactgtgcc ttcaagagac caaatgttca
       310        320        330        340        350        360
gagaacaaac taccagctga acttcaggag ctgcctggac tctctcatca atactggtca
       370        380        390        400        410        420
gctccttcgg acaaggaagg gtacagtggc gtgggcctgc tttcccgcca gtgcccactc
       430        440        450        460        470        480
aaagtttctt acggcatagg cgatgaggag catgatcagg aaggccgggt gattgtggct
       490        500        510        520        530        540
gaatttgact cgtttgtgct ggtaacagca tatgtaccta atgcaggccg aggtctggta
       550        560        570        580        590        600
cgactggagt accggcagcg ctgggatgaa gcctttcgca agttcctgaa gggcctggct
       610        620        630        640        650        660
tcccgaaagc cccttgtgct gtgtggagac ctcaatgtgg cacatgaaga aattgacctt
       670        680        690        700        710        720
cgcaacccca aggggaacaa aaagaatgct ggcttcacgc cacaagagcg ccaaggcttc
       730        740        750        760        770        780
ggggaattac tgcaggctgt gccactggct gacagcttta ggcacctcta ccccaacaca
       790        800        810        820        830        840
ccctatgcct acaccttttg gacttatatg atgaatgctc gatccaagaa tgttggttgg
       850        860        870        880        890        900
cgccttgatt actttttgtt gtcccactct ctgttacctg cattgtgtga cagcaagatc
       910        920        930        940        950
cgttccaagg ccctcggcag tgatcactgt cctatcaccc tatacctagc actgtga

Last modification date: Oct. 2, 2011