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Molecular and Cellular Biology, June 2009, p. 3344-3354, Vol. 29, No. 12
0270-7306/09/$08.00+0     doi:10.1128/MCB.00115-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Human DNA Polymerase {eta} Is Required for Common Fragile Site Stability during Unperturbed DNA Replication{triangledown}

Laurie Rey,1,2 Julia M. Sidorova,3,{ddagger} Nadine Puget,1,2,{ddagger} François Boudsocq,1,2,{dagger} Denis S. F. Biard,4 Raymond J. Monnat Jr.,3,5 Christophe Cazaux,1,2 and Jean-Sébastien Hoffmann1,2*

CNRS, IPBS (Institute of Pharmacology and Structural Biology), 205 Route de Narbonne, F-31077 Toulouse, France,1 University of Toulouse, UPS, F-31077 Toulouse, France,2 Department of Pathology,3 Department of Genome Sciences, University of Washington, Seattle, Washington 98195-7705,5 CEA-DSV-IRCM/INSERM U935, Institut A. Lwoff-CNRS, 7 Rue Guy Moquet, BP 8, 94801 Villejuif, France4

Received 26 January 2009/ Returned for modification 26 February 2009/ Accepted 9 April 2009

Human DNA polymerase {eta} (Pol {eta}) modulates susceptibility to skin cancer by promoting translesion DNA synthesis (TLS) past sunlight-induced cyclobutane pyrimidine dimers. Despite its well-established role in TLS synthesis, the role of Pol {eta} in maintaining genome stability in the absence of external DNA damage has not been well explored. We show here that short hairpin RNA-mediated depletion of Pol {eta} from undamaged human cells affects cell cycle progression and the rate of cell proliferation and results in increased spontaneous chromosome breaks and common fragile site expression with the activation of ATM-mediated DNA damage checkpoint signaling. These phenotypes were also observed in association with modified replication factory dynamics during S phase. In contrast to that seen in Pol {eta}-depleted cells, none of these cellular or karyotypic defects were observed in cells depleted for Pol {iota}, the closest relative of Pol {eta}. Our results identify a new role for Pol {eta} in maintaining genomic stability during unperturbed S phase and challenge the idea that the sole functional role of Pol {eta} in human cells is in TLS DNA damage tolerance and/or repair pathways following exogenous DNA damage.

* Corresponding author. Mailing address: CNRS, UMR 5089, 205 Route de Narbonne, F-31077 Toulouse, France. Phone: 33 5 61 17 59 75. Fax: 33 5 61 17 59 94. E-mail: jseb{at}ipbs.fr

{triangledown} Published ahead of print on 20 April 2009.

{dagger} Present address: CNRS, UMR 5099, LBME, and Université Paul Sabatier, F-31062 Toulouse, France.

{ddagger} J.M.S. and N.P. contributed equally to this work.

Molecular and Cellular Biology, June 2009, p. 3344-3354, Vol. 29, No. 12
0270-7306/09/$08.00+0     doi:10.1128/MCB.00115-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Mudrak, S. V., Welz-Voegele, C., Jinks-Robertson, S. (2009). The Polymerase {eta} Translesion Synthesis DNA Polymerase Acts Independently of the Mismatch Repair System To Limit Mutagenesis Caused by 7,8-Dihydro-8-Oxoguanine in Yeast. Mol. Cell. Biol. 29: 5316-5326 [Abstract] [Full Text]  


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