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Identification and characterization of a Drosophila ortholog of WRN exonuclease that is required to maintain genome integrity

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Identification and characterization of a Drosophila ortholog of WRN exonuclease that is required to maintain genome integrity. / Saunders, R. D. C.; Boubriak, I.; Clancy, D. J. et al.
In: Aging Cell, Vol. 7, No. 3, 06.2008, p. 418-425.

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Saunders RDC, Boubriak I, Clancy DJ, Cox LS. Identification and characterization of a Drosophila ortholog of WRN exonuclease that is required to maintain genome integrity. Aging Cell. 2008 Jun;7(3):418-425. doi: 10.1111/j.1474-9726.2008.00388.x

Author

Saunders, R. D. C. ; Boubriak, I. ; Clancy, D. J. et al. / Identification and characterization of a Drosophila ortholog of WRN exonuclease that is required to maintain genome integrity. In: Aging Cell. 2008 ; Vol. 7, No. 3. pp. 418-425.

Bibtex

@article{28c4f423579b4668bb2770fcdde271f4,
title = "Identification and characterization of a Drosophila ortholog of WRN exonuclease that is required to maintain genome integrity",
abstract = "The premature human aging Werner syndrome (WS) is caused by mutation of the RecQ-family WRN helicase, which is unique in possessing also 3'-5' exonuclease activity. WS patients show significant genomic instability with elevated cancer incidence. WRN is implicated in restraining illegitimate recombination, especially during DNA replication. Here we identify a Drosophila ortholog of the WRN exonuclease encoded by the CG7670 locus. The predicted DmWRNexo protein shows conservation of structural motifs and key catalytic residues with human WRN exonuclease, but entirely lacks a helicase domain. Insertion of a piggyBac element into the 5' UTR of CG7670 severely reduces gene expression. DmWRNexo mutant flies homozygous for this insertional allele of CG7670 are thus severely hypomorphic; although adults show no gross morphological abnormalities, females are sterile. Like human WS cells, we show that the DmWRNexo mutant flies are hypersensitive to the topoisomerase I inhibitor camptothecin. Furthermore, these mutant flies show highly elevated rates of mitotic DNA recombination resulting from excessive reciprocal exchange. This study identifies a novel WRN ortholog in flies and demonstrates an important role for WRN exonuclease in maintaining genome stability.",
keywords = "exonuclease, Drosophila , genome stability , homologous recombination, Werner syndrome, WRN",
author = "Saunders, {R. D. C.} and I. Boubriak and Clancy, {D. J.} and Cox, {L. S.}",
note = "Jun Identification and characterization of a Drosophila ortholog of WRN exonuclease that is required to maintain genome integrity Saunders, Robert D. C. Boubriak, Ivan Clancy, David J. Cox, Lynne S.",
year = "2008",
month = jun,
doi = "10.1111/j.1474-9726.2008.00388.x",
language = "English",
volume = "7",
pages = "418--425",
journal = "Aging Cell",
issn = "1474-9726",
publisher = "Wiley-Blackwell",
number = "3",

}

RIS

TY - JOUR

T1 - Identification and characterization of a Drosophila ortholog of WRN exonuclease that is required to maintain genome integrity

AU - Saunders, R. D. C.

AU - Boubriak, I.

AU - Clancy, D. J.

AU - Cox, L. S.

N1 - Jun Identification and characterization of a Drosophila ortholog of WRN exonuclease that is required to maintain genome integrity Saunders, Robert D. C. Boubriak, Ivan Clancy, David J. Cox, Lynne S.

PY - 2008/6

Y1 - 2008/6

N2 - The premature human aging Werner syndrome (WS) is caused by mutation of the RecQ-family WRN helicase, which is unique in possessing also 3'-5' exonuclease activity. WS patients show significant genomic instability with elevated cancer incidence. WRN is implicated in restraining illegitimate recombination, especially during DNA replication. Here we identify a Drosophila ortholog of the WRN exonuclease encoded by the CG7670 locus. The predicted DmWRNexo protein shows conservation of structural motifs and key catalytic residues with human WRN exonuclease, but entirely lacks a helicase domain. Insertion of a piggyBac element into the 5' UTR of CG7670 severely reduces gene expression. DmWRNexo mutant flies homozygous for this insertional allele of CG7670 are thus severely hypomorphic; although adults show no gross morphological abnormalities, females are sterile. Like human WS cells, we show that the DmWRNexo mutant flies are hypersensitive to the topoisomerase I inhibitor camptothecin. Furthermore, these mutant flies show highly elevated rates of mitotic DNA recombination resulting from excessive reciprocal exchange. This study identifies a novel WRN ortholog in flies and demonstrates an important role for WRN exonuclease in maintaining genome stability.

AB - The premature human aging Werner syndrome (WS) is caused by mutation of the RecQ-family WRN helicase, which is unique in possessing also 3'-5' exonuclease activity. WS patients show significant genomic instability with elevated cancer incidence. WRN is implicated in restraining illegitimate recombination, especially during DNA replication. Here we identify a Drosophila ortholog of the WRN exonuclease encoded by the CG7670 locus. The predicted DmWRNexo protein shows conservation of structural motifs and key catalytic residues with human WRN exonuclease, but entirely lacks a helicase domain. Insertion of a piggyBac element into the 5' UTR of CG7670 severely reduces gene expression. DmWRNexo mutant flies homozygous for this insertional allele of CG7670 are thus severely hypomorphic; although adults show no gross morphological abnormalities, females are sterile. Like human WS cells, we show that the DmWRNexo mutant flies are hypersensitive to the topoisomerase I inhibitor camptothecin. Furthermore, these mutant flies show highly elevated rates of mitotic DNA recombination resulting from excessive reciprocal exchange. This study identifies a novel WRN ortholog in flies and demonstrates an important role for WRN exonuclease in maintaining genome stability.

KW - exonuclease

KW - Drosophila

KW - genome stability

KW - homologous recombination

KW - Werner syndrome

KW - WRN

UR - http://www.scopus.com/inward/record.url?scp=43449117492&partnerID=8YFLogxK

U2 - 10.1111/j.1474-9726.2008.00388.x

DO - 10.1111/j.1474-9726.2008.00388.x

M3 - Journal article

VL - 7

SP - 418

EP - 425

JO - Aging Cell

JF - Aging Cell

SN - 1474-9726

IS - 3

ER -