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Identification of BRCA1-IRIS, a BRCA1 locus product

Nature Cell Biology volume 6, pages 954–967 (2004)Cite this article

Abstract

Breast cancer is the most common malignancy among women, and mutations in the BRCA genes produce increased susceptibility to these malignancies in certain families. Here we identify BRCA1-IRIS as a 1,399-amino-acid BRCA1 gene product encoded by an uninterrupted open reading frame that extends from codon 1 of the known BRCA1 open reading frame to a termination point 34 triplets into intron 11. Unlike full-length BRCA1 (p220), BRCA1-IRIS is exclusively chromatin-associated, fails to interact with BARD1 in vivo or in vitro and exhibits unique nuclear immunostaining. Unlike BRCA1FL (or p220), BRCA1-IRIS also co-immunoprecipitated with DNA-replication-licensing proteins and with known replication initiation sites. Suppression of BRCA1-IRIS expression hindered the normal departure of geminin from pre-replication complexes, and depressed the rate of cellular DNA replication and possibly initiation-related synthesis. In contrast, BRCA1-IRIS overexpression stimulated DNA replication. These data imply that endogenous BRCA1-IRIS positively influences the DNA replication initiation machinery.

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Figure 1: Identification of BRCA1-IRIS.
Figure 2: Cloning of BRCA1-IRIS cDNA.
Figure 3: Localization and expression of BRCA1-IRIS and p220 in human cells and tissues.
Figure 4: Analysis of biological and biochemical properties of BRCA1-IRIS.
Figure 5: BRCA1-IRIS- and BRCA1-IRIS-associated proteins bind to DNA-replication-initiation sites in vivo.
Figure 6: Behaviour of certain pre-replication complex proteins and BRCA1-IRIS.
Figure 7: The effect of BRCA1-IRIS on DNA replication.

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Acknowledgements

We wish to thank R. Laskey for his comments following the reading of this manuscript. We are also grateful to V. Joukov for sharing his IMR90 cDNA library and D. Avni, for sharing the results of his unpublished data with us. We also thank J. Lane for technical assistance. This work was supported by grants from the National Cancer Institute (N.C.I.). W.E. was supported, in part, by a European Molecular Biology Organization (EMBO) Fellowship and in part by a “Massachusetts Department of Public Health Breast Cancer Research Grant”, number 30481126109. W.E. is currently supported by a grant from the N.C.I. Specialized Program of Research Excellence (SPORE) in breast cancer research at the Dana-Farber/Harvard Cancer Center.

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  1. The Dana-Farber Cancer Institute and the Harvard Medical School, 44 Binney St, Boston, 02115, MA, USA

    Wael M. ElShamy & David M. Livingston

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Correspondence to Wael M. ElShamy or David M. Livingston.

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ElShamy, W., Livingston, D. Identification of BRCA1-IRIS, a BRCA1 locus product. Nat Cell Biol 6, 954–967 (2004). https://doi.org/10.1038/ncb1171

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