Splicing regulator SC35 is essential for genomic stability and cell proliferation during mammalian organogenesis.
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.
Xiao
Ran
R
Department of Surgery/Urology, Children's Hospital of Boston, Harvard Medical School, 300 Longwood Ave., Boston, MA 02115, USA.
Sun
Ye
Y
Ding
Jian-Hua
JH
Lin
Shengrong
S
Rose
Dave W
DW
Rosenfeld
Michael G
MG
Fu
Xiang-Dong
XD
Li
Xue
X
D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D049109:Cell Proliferation; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D016195:G2 Phase; D005816:Genetic Complementation Test; D042822:Genomic Instability; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism*; D038081:Organogenesis; D010902:Pituitary Gland / Q000002:abnormalities / Q000166:cytology / Q000196:embryology; D012261:Ribonucleoproteins / Q000172:deficiency / Q000378:metabolism*; D000068103:Serine-Arginine Splicing Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D009687:Nuclear Proteins; D012261:Ribonucleoproteins; C499372:SRSF2 protein, mouse; D016159:Tumor Suppressor Protein p53; D000068103:Serine-Arginine Splicing Factors