A nuclear 3′–5′ exonuclease proofreads for the exonuclease-deficient DNA polymerase α

Brown, Kevin R.; Weatherdon, Krista L; Galligan, Carole L.; Skalski, Violetta

doi:10.1016/s1568-7864(02)00115-5

Cited by 11 publications

(8 citation statements)

References 32 publications

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“…ExoN is reported to interact with DNA pol α and may supply it with proofreading capability (Brown et al 2002;Perrino and Loeb 1990;Skalski et al 2000). ExoN upregulation by approximately sixfold in araC-resistant leukemia cells suggests that these cancer cells overcome drug treatment through efficient removal of drug-induced mismatches, and hence ExoN is likely to be a clinically relevant target in cancer (Skalski et al 2000) and possibly age-related accumulation of genetic damage.…”

Section: Nucleases Involved In Dna Replicationmentioning

confidence: 99%

The role of DNA exonucleases in protecting genome stability and their impact on ageing

Mason

Cox

2011

AGE

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Exonucleases are key enzymes involved in many aspects of cellular metabolism and maintenance and are essential to genome stability, acting to cleave DNA from free ends. Exonucleases can act as proofreaders during DNA polymerisation in DNA replication, to remove unusual DNA structures that arise from problems with DNA replication fork progression, and they can be directly involved in repairing damaged DNA. Several exonucleases have been recently discovered, with potentially critical roles in genome stability and ageing. Here we discuss how both intrinsic and extrinsic exonuclease activities contribute to the fidelity of DNA polymerases in DNA replication. The action of exonucleases in processing DNA intermediates during normal and aberrant DNA replication is then assessed, as is the importance of exonucleases in repair of double-strand breaks and interstrand crosslinks. Finally we examine how exonucleases are involved in maintenance of mitochondrial genome stability. Throughout the review, we assess how nuclease mutation or loss predisposes to a range of clinical diseases and particularly ageing.

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Section: Nucleases Involved In Dna Replicationmentioning

confidence: 99%

The role of DNA exonucleases in protecting genome stability and their impact on ageing

Mason

Cox

2011

AGE

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“…Human ExoN possesses 3′→5′ exonuclease activity which excises nucleotides from ssDNA and dsDNA in a nonprocessive way [154]. Fidelity and elongation from mismatched base pairs by Pol α are increased in the presence of ExoN [155].…”

Section: Proofreading By 3′→5′ Exonucleasesmentioning

confidence: 99%

DNA repair nucleases

Marti

Fleck

2004

Cellular and Molecular Life Sciences (CMLS)

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Stability of DNA largely depends on accuracy of repair mechanisms, which remove structural anomalies induced by exogenous and endogenous agents or introduced by DNA metabolism, such as replication. Most repair mechanisms include nucleolytic processing of DNA, where nucleases cleave a phosphodiester bond between a deoxyribose and a phosphate residue, thereby producing 5'-terminal phosphate and 3'-terminal hydroxyl groups. Exonucleases hydrolyse nucleotides from either the 5' or 3' end of DNA, while endonucleases incise internal sites of DNA. Flap endonucleases cleave DNA flap structures at or near the junction between single-stranded and double-stranded regions. DNA nucleases play a crucial role in mismatch repair, nucleotide excision repair, base excision repair and double-strand break repair. In addition, nucleolytic repair functions are required during replication to remove misincorporated nucleotides, Okazaki fragments and 3' tails that may be formed after repair of stalled replication forks.

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“…It was previously shown that recombinant TREX1/DNase III can edit a 3Ј mismatch in an in vitro base excision repair system reconstituted with Pol␤ (14). Other 3Ј exonuclease activities have also been described that can apparently proofread for Pol␣ or Pol␤ (3,43). Furthermore, a modest 3Ј35Ј exonuclease activity of the APE1/HAP1 apurinic-apyrimidinic (AP) endonuclease, which interacts with Pol␤ (2), can apparently edit mismatched nucleotides that are erroneously incorporated by Pol␤, in addition to its major incision role in base excision repair (5,51), at least in vitro, but the significance of this exonuclease activity remains unclear (6,22,50).…”

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confidence: 99%

Gene-Targeted Mice Lacking the Trex1 (DNase III) 3′→5′ DNA Exonuclease Develop Inflammatory Myocarditis

Morita

Stamp

Robins

et al. 2004

Molecular and Cellular Biology

334

280

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TREX1, originally designated DNase III, was isolated as a major nuclear DNA-specific 335 exonuclease that is widely distributed in both proliferating and nonproliferating mammalian tissues. The cognate cDNA shows homology to the editing subunit of the Escherichia coli replicative DNA polymerase III holoenzyme and encodes an exonuclease which was able to serve a DNA-editing function in vitro, promoting rejoining of a 3 mismatched residue in a reconstituted DNA base excision repair system. Here we report the generation of genetargeted Trex1؊/؊ mice. The null mice are viable and do not show the increase in spontaneous mutation frequency or cancer incidence that would be predicted if Trex1 served an obligatory role of editing mismatched 3 termini generated during DNA repair or DNA replication in vivo. Unexpectedly, Trex1 ؊/؊ mice exhibit a dramatically reduced survival and develop inflammatory myocarditis leading to progressive, often dilated, cardiomyopathy and circulatory failure.Two distinct nuclear exonucleases account for the major part of the total exonucleolytic activity on DNA observed in mammalian cell extracts (24, 25). They were identified as a 3Ј35Ј exonuclease acting preferentially on single-stranded DNA and a 5Ј33Ј exonuclease specific for double-stranded DNA that could remove a single-stranded 5Ј overhang as an oligonucleotide. These nuclear enzymes were designated DNase III and DNase IV, as they are distinct from the pancreatic and macrophage lysosomal DNA endonucleases DNase I and DNase II. DNase IV was later renamed flap endonuclease 1 (FEN1) (23), and its main function is processing displaced 5Ј single strands that arise during lagging-strand DNA replication, as well as during DNA repair, recombination, and triplet repeat expansion. The elimination of Fen1 activity leads to early embryonic lethality in mice, consistent with an essential role of the enzyme in DNA replication (20). In contrast, DNase III is expressed at similar levels in nonproliferating and proliferating tissues; it was isolated as the major nuclear 3Ј35Ј DNA exonuclease from the adult rabbit liver (14) and also from the calf thymus and human myoblasts, where it was designated TREX1 (37, 38).The human TREX1/DNase III cDNA (14, 29) shares amino acid sequence homology with the Escherichia coli DnaQ/MutD editing subunit of the replicative DNA polymerase III holoenzyme, which can increase the fidelity of an exonuclease-deficient mammalian DNA polymerase in vitro (36). The TREX1/ DNase III cDNA encodes a nonprocessive 3Ј35Ј DNA-specific exonuclease, with a preference for single-stranded DNA or mispaired 3Ј termini; like the native protein isolated from mammalian cells, it forms homodimers (14, 29, 30). Since two of the major mammalian nuclear DNA polymerases, Pol␣ and Pol␤, do not have an intrinsic 3Ј exonuclease function, it was proposed that TREX1/DNase III may serve to edit mismatched deoxyribonucleotides during lagging-strand DNA synthesis or gap filling in DNA base excision repair, which are conducted by Pol␣ and Pol␤, respectively...

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A nuclear 3′–5′ exonuclease proofreads for the exonuclease-deficient DNA polymerase α

Cited by 11 publications

References 32 publications

The role of DNA exonucleases in protecting genome stability and their impact on ageing

The role of DNA exonucleases in protecting genome stability and their impact on ageing

DNA repair nucleases

Gene-Targeted Mice Lacking the Trex1 (DNase III) 3′→5′ DNA Exonuclease Develop Inflammatory Myocarditis

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