the endonuclease iv family of apurinic/apyrimidinic endonucleases

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    Mutation Research 705 (2010) 217227

    Contents lists available at ScienceDirect

    Mutation Research/Review

    journal homepage: www.e lse.eContents

    1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

    2. Sources and biological consequences of AP sites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218

    3. Repair of AP sites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218

    4. E. coli endonuclease IV. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219

    5. S. cerevisiae Apn1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222

    5.1. The role of Apn1 in mitochondrial BER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223

    6. S. pombe Apn1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223

    7. C. elegans APN-1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

    8. Conclusions and future directions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

    Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225

    References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225

    1. Introduction

    Genomic DNA is constantly damaged by a variety of endoge-nous and exogenous agents. Base damage is one of the mostcommon forms of DNA damage. Oxidation, alkylation anddeamination of bases can disrupt base pairing and promotemutagenesis by leading to misincorporation errors during DNAreplication. It is therefore critical for cells to recognize andfaithfully repair these lesions to avoid cancer and premature aging.All kingdoms of life possess apurinic/apyrimidinic (AP) endonu-cleases, which participate in processing base lesions at various

    steps. AP endonucleases are named for their ability to cleave APsites in DNA, which are formed when DNA glycosylases cleavedamaged bases at the N-glycosidic bond. Some AP endonucleasesare also endowed with the ability to directly incise the DNA strandupstream of the primary lesion in a process termed nucleotideincision repair (NIR), leaving the damaged base on a 50 ap [1].Finally, AP endonucleases have 30 phosphodiesterase activity,which can process damaged 30 ends on single-strand breaks, and3050 exonuclease activity which can remove nucleotides from theend of a nick [2,3].

    The two families of AP endonucleases are named for theirarchetypal Escherichia colimembers, endonuclease IV (EndoIV) andexonuclease III (ExoIII). The two families are structurally unrelated,indicating that they evolved independently and not from acommon ancestor. Table 1 summarizes the key model organisms

    A R T I C L E I N F O

    Article history:

    Received 27 April 2010

    Received in revised form 3 July 2010

    Accepted 14 July 2010

    Available online 3 August 2010

    Keywords:

    Endonucleases

    Base excision repair

    Nucleotide incision repair

    Genomic stability

    Yeast

    C. elegans

    A B S T R A C T

    Apurinic/apyrimidinic (AP) endonucleases are versatile DNA repair enzymes that possess a variety of

    nucleolytic activities, including endonuclease activity at AP sites, 30 phosphodiesterase activity that canremove a variety of ligation-blocking lesions from the 30 end of DNA, endonuclease activity on oxidativeDNA lesions, and 30 to 50 exonuclease activity. There are two families of AP endonucleases, named for thebacterial counterparts endonuclease IV (EndoIV) and exonuclease III (ExoIII). While ExoIII family

    members are present in all kingdoms of life, EndoIV members exist in lower organisms but are curiously

    absent in plants, mammals and some other vertebrates. Here, we review recent research on these

    enzymes, focusing primarily on the EndoIV family. We address the role(s) of EndoIV members in DNA

    repair and discuss recent ndings from eachmodel organism in which the enzymes have been studied to

    date.

    2010 Elsevier B.V. All rights reserved.

    * Corresponding author. Tel.: +1 514 252 3400x4684; fax: +1 514 252 3430.

    E-mail address: dramotar.hmr@ssss.gouv.qc.ca (D. Ramotar).

    1383-5742/$ see front matter 2010 Elsevier B.V. All rights reserved.doi:10.1016/j.mrrev.2010.07.003Mini-review

    The endonuclease IV family of apurinic

    James M. Daley, Chadi Zakaria, Dindial Ramotar *

    Centre de Recherche, Hopital Maisonneuve-Rosemont, Universite de Montreal, 5415 de

    Communi ty address : wwwpyrimidinic endonucleases

    ssomption, Montreal, QC H1T 2M4, Canada

    s in Mutation Research

    vier .com/ locate / rev iewsmrlsev ier .com/ locate /mutres

  • J.M. Daley et al. /Mutation Research 705 (2010) 217227218in which EndoIV homologs have been identied and studied. InSaccharomyces cerevisiae, the EndoIV homolog Apn1 is responsiblefor the vastmajority of AP endonuclease activity in the cell [2,4]. AnEndoIV homolog (APN-1) also signicantly contributes to DNArepair in Caenorhabditis elegans [5]. In Schizosaccharomyces pombe,an EndoIV homolog exists but seems to play only a backup role inDNA repair [6]. EndoIV family members are also present in somesh (Danio rerio) and frogs (Xenopus tropicalis) but have not yetbeen studied in these organisms. EndoIV homologs are curiouslyabsent from higher organisms including insects and mammals.These organisms instead depend solely on ExoIII family members,such as human APE1, for AP endonuclease activity. Unlike EndoIV,ExoIII family members exist in all kingdoms of life. Like humancells, E. coli utilizes ExoIII as its major AP endonuclease, but alsoinduces EndoIV under stress conditions [79]. In contrast, the yeastExoIII homolog, Apn2, constitutes only aminor portion (
  • [(Fig._1)TD$FIG]

    lated

    ed b

    J.M. Daley et al. /Mutation Research 705 (2010) 217227 219endonuclease 1 (FEN-1) and, as in SP-BER, a DNA ligase seals thenick.

    AP sites can also be cleaved by AP lyases [48]. E. coliendonuclease III (EndoIII) is the prototypical AP lyase, and manyDNA glycosylases in higher organisms have additional AP lyaseactivity [4951]. Unlike AP endonucleases, AP lyases cleave on the30 side of the AP site through a b-elimination reaction to producean a,b-unsaturated aldehyde [5254]. This product blocks DNArepair synthesis and must therefore be removed by a 30

    phosphodiesterase before repair can proceed [11]. Most APendonucleases possess this activity and are capable of removinga variety of 30 blocking groups in addition to a,b-unsaturated

    Fig. 1.General model for AP endonuclease involvement in base excision repair and reor removed by glycosylases to form AP sites (right). The damaged base is resynthesiz

    are also repaired by the AP endonucleases.aldehydes, including 30 phosphates and 30 phosphoglycolates,which are present at single-strand breaks caused by oxidizingagents (Fig. 2B) [3,15,55]. Genetic data in E. coli and S. cerevisiaesuggests that AP sites are mainly processed by the AP endonu-cleases, with the AP lyases serving as a backupmechanism [50,5658]. The situation appears to be reversed in other organisms suchas S. pombe, however, where the lyase pathway predominates[59,60].

    4. E. coli endonuclease IV

    The rst indication regarding the presence of a specic class ofenzymes capable of processing AP sites came from studies in E. coli.ExoIII was the rst AP endonuclease discovered and accounts for90% of the total AP endonuclease activity in the cell [61]. ExoIIIwas rst described as a 30 to 50 exonuclease, and it was originallythought that the major cellular AP endonuclease activity was dueto a separate enzyme termed endonuclease II [62,63]. Later, it wasfound that the same mutation disrupts both exonuclease andendonuclease activities, and in 1976 the two activities wereattributed to the same enzyme, ExoIII [8,64]. ExoIII requires Mg2+

    and is therefore EDTA-sensitive [65]. ExoIII is also heat sensitive, asit is inactivated rapidly upon incubation of the puried protein atmoderately high temperatures [66,67]. ExoIII possesses three othercatalytic activities in addition to its AP endonuclease activity. It is a30 to 50 exonuclease specic for dsDNA, allowing it to degrade bluntends, 50 overhangs or nicks to produce segments of ssDNA [68].This activity is not observed on dsDNA with 30 overhangs that areover four bases long or on ssDNA [68]. ExoIII can also remove 30

    phosphates to generate 30 OH termini, and has RNase H activitythat degrades RNA in DNA-RNA hybrids [68].

    The hunt for a second

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