TY - JOUR
T1 - CARM1 automethylation is controlled at the level of alternative splicing
AU - Wang, Lu
AU - Charoensuksai, Purin
AU - Watson, Nikole J.
AU - Wang, Xing
AU - Zhao, Zibo
AU - Coriano, Carlos G.
AU - Kerr, Leslie R.
AU - Xu, Wei
N1 - Funding Information:
National Institutes of Health [RO1CA125387]; National Scientific and Engineering Research Council (NSERC) of Canada [Grant #288318 to L.K.]; Trent University Internal Research Grants (to L.K.); DOD ERA of HOPE Scholar Award [Grant #W81XWYH-11-1-0237 to W.X.]; Villas Associate Award (to W.X.); AOF (to C.G.C.); Royal Thai Government Scholarship (to P.C.). Funding for open access charge: DOD grant [W81XWYH-11-1-0237 to W.X].
PY - 2013/8
Y1 - 2013/8
N2 - Co-activator-associated arginine methyltransferase 1 (CARM1) is subjected to multiple post-translational modifications. Our previous finding that automethylation of CARM1 is essential for regulation of transcription and pre-mRNA splicing prompted us to investigate how automethylation is regulated. Here, we report that automethylation is regulated by alternative splicing of CARM1 mRNA to remove exon 15, containing the automethylation site. Specifically, we find that two major alternative transcripts encoding full-length CARM1 (CARM1FL) and CARM1 with exon 15 deleted (CARM1ΔE15) exist in cells, and each transcript produces the expected protein. Further biochemical characterizations of the automethylation-defective mutant and CARM1ΔE15 reveal overlapping yet different properties. Interestingly, other arginine methylation substrates also have missing exons encompassing the site(s) of methylation, suggesting that protein arginine methylation level may, in general, be controlled by the alternative splicing mechanism. Finally, we observed differential distribution of CARM1FL and CARM1ΔE15 in epithelial and stromal cells in normal mouse mammary gland. Thus, alternative splicing not only serves as the determinant for CARM1 automethylation but also generates cell type-specific isoforms that might regulate normal ERα biology in the mammary gland.
AB - Co-activator-associated arginine methyltransferase 1 (CARM1) is subjected to multiple post-translational modifications. Our previous finding that automethylation of CARM1 is essential for regulation of transcription and pre-mRNA splicing prompted us to investigate how automethylation is regulated. Here, we report that automethylation is regulated by alternative splicing of CARM1 mRNA to remove exon 15, containing the automethylation site. Specifically, we find that two major alternative transcripts encoding full-length CARM1 (CARM1FL) and CARM1 with exon 15 deleted (CARM1ΔE15) exist in cells, and each transcript produces the expected protein. Further biochemical characterizations of the automethylation-defective mutant and CARM1ΔE15 reveal overlapping yet different properties. Interestingly, other arginine methylation substrates also have missing exons encompassing the site(s) of methylation, suggesting that protein arginine methylation level may, in general, be controlled by the alternative splicing mechanism. Finally, we observed differential distribution of CARM1FL and CARM1ΔE15 in epithelial and stromal cells in normal mouse mammary gland. Thus, alternative splicing not only serves as the determinant for CARM1 automethylation but also generates cell type-specific isoforms that might regulate normal ERα biology in the mammary gland.
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U2 - 10.1093/nar/gkt415
DO - 10.1093/nar/gkt415
M3 - Article
C2 - 23723242
AN - SCOPUS:84881527686
SN - 0305-1048
VL - 41
SP - 6870
EP - 6880
JO - Nucleic acids research
JF - Nucleic acids research
IS - 14
ER -