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Molecular and Cellular Biology, August 2007, p. 5393-5402, Vol. 27, No. 15
0270-7306/07/$08.00+0     doi:10.1128/MCB.00288-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Splicing Regulator SC35 Is Essential for Genomic Stability and Cell Proliferation during Mammalian Organogenesis

Ran Xiao,^1,2, Ye Sun,^1, Jian-Hua Ding,^2, Shengrong Lin,^2,3, Dave W. Rose,⁴ Michael G. Rosenfeld,^4,5 Xiang-Dong Fu,^2* and Xue Li^1*

Department of Surgery/Urology and Department of Pathology, Children's Hospital of Boston, Harvard Medical School, 300 Longwood Ave., Boston, Massachusetts 02115,¹ Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, California 92093,² Department of Pathology,³ Department of Medicine,⁴ Howard Hughes Medical Institute, University of California, San Diego, 9500 Gilman Dr., La Jolla, California 92093⁵

Received 16 February 2007/ Returned for modification 30 March 2007/ Accepted 15 May 2007

The members of the SR family of splicing regulators were initially characterized for their critical roles in constitutive and regulated splicing. They are implicated in different aspects of gene expression processes, including transcription, RNA stability, mRNA transport, and translational control. While knockout studies have demonstrated their essential functions during animal development, the pathway(s) leading to a specific cellular phenotype remains poorly understood. We report here that the SR protein SC35 controls cell proliferation during pituitary gland development but is completely dispensable in terminal differentiated mature cardiomyocytes in mice. We show that loss of SC35 in mouse embryonic fibroblasts induces G₂/M cell cycle arrest and genomic instability, resulting at least in part from p53 hyperphosphorylation and hyperacetylation. While p53 hyperphosphorylation appears related to ATM activation, its hyperacetylation has been attributed to the increased expression of the acetyltransferase gene p300 and the aberrant splicing of the deacetylase gene SirT1. These findings reveal the involvement of SC35 in specific pathways in regulating cell proliferation and genomic stability during mammalian organogenesis and suggest its potential function in tumorigenesis.

Published ahead of print on 25 May 2007.

These authors contributed equally to this work.

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