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Molecular and Cellular Biology, June 2009, p. 2982-2996, Vol. 29, No. 11
0270-7306/09/$08.00+0     doi:10.1128/MCB.00042-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

A Mouse PRMT1 Null Allele Defines an Essential Role for Arginine Methylation in Genome Maintenance and Cell Proliferation{triangledown}

Zhenbao Yu,1 Taiping Chen,2 Josée Hébert,3 En Li,2 and Stéphane Richard1*

Terry Fox Molecular Oncology Group and Bloomfield Center for Research on Aging, Segal Cancer Centre, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, and Departments of Oncology and Medicine, McGill University, Montréal, Québec H3T 1E2, Canada,1 Epigenetics Program, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139,2 Leukemia Cell Bank of Quebec and Division of Hematology, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada, and Department of Medicine, Université de Montréal, Montreal, Quebec H3C 3J7, Canada3

Received 10 January 2009/ Returned for modification 19 February 2009/ Accepted 9 March 2009

Protein arginine methyltransferase 1 (PRMT1) is the major enzyme that generates monomethylarginine and asymmetrical dimethylarginine. We report here a conditional null allele of PRMT1 in mice and that the loss of PRMT1 expression leads to embryonic lethality. Using the Cre/lox-conditional system, we show that the loss of PRMT1 in mouse embryonic fibroblasts (MEFs) leads to the loss of arginine methylation of substrates harboring a glycine-arginine rich motif, including Sam68 and MRE11. The loss of PRMT1 in MEFs leads to spontaneous DNA damage, cell cycle progression delay, checkpoint defects, aneuploidy, and polyploidy. We show using a 4-hydroxytamoxifen-inducible Cre that the loss of PRMT1 in MEFs leads to a higher incidence of chromosome losses, gains, structural rearrangements, and polyploidy, as documented by spectral karyotyping. Using PRMT1 small interfering RNA in U2OS cells, we further show that PRMT1-deficient cells are hypersensitive to the DNA damaging agent etoposide and exhibit a defect in the recruitment of the homologous recombination RAD51 recombinase to DNA damage foci. Taken together, these data show that PRMT1 is required for genome integrity and cell proliferation. Our findings also suggest that arginine methylation by PRMT1 is a key posttranslational modification in the DNA damage response pathway in proliferating mammalian cells.

* Corresponding author. Mailing address: Segal Cancer Centre, 3755 Côte Ste.-Catherine Road, Montréal, Québec H3T 1E2, Canada. Phone: (514) 340-8260. Fax: (514) 340-8295. E-mail: stephane.richard{at}mcgill.ca

{triangledown} Published ahead of print on 16 March 2009.

Molecular and Cellular Biology, June 2009, p. 2982-2996, Vol. 29, No. 11
0270-7306/09/$08.00+0     doi:10.1128/MCB.00042-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Michaud-Levesque, J., Richard, S. (2009). Thrombospondin-1 Is a Transcriptional Repression Target of PRMT6. J. Biol. Chem. 284: 21338-21346 [Abstract] [Full Text]  


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