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Open Access Highly Accessed Research article

Loss of CARM1 is linked to reduced HuR function in replicative senescence

Lijun Pang1, Haiyan Tian1, Na Chang1, Jie Yi1, Lixiang Xue1, Bin Jiang1, Myriam Gorospe2, Xiaowei Zhang1* and Wengong Wang1*

Author Affiliations

1 Department of Biochemistry and Molecular Biology, Peking University health Science Center, 38 Xueyuan Road, Beijing 100191, P. R. China

2 Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of health, 251 Bayview Blvd., Baltimore, MD 21224, USA

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BMC Molecular Biology 2013, 14:15  doi:10.1186/1471-2199-14-15

Published: 9 July 2013

Abstract

Background

The co-activator-associated arginine methyltransferase 1 (CARM1) catalyzes the methylation of HuR. However, the functional impact of this modification is not fully understood. Here, we investigated the influence of HuR methylation by CARM1 upon the turnover of HuR target mRNAs encoding senescence-regulatory proteins.

Results

Changing the methylation status of HuR in HeLa cells by either silencing CARM1 or mutating the major methylation site (R217K) greatly diminished the effect of HuR in regulating the turnover of mRNAs encoding cyclin A, cyclin B1, c-fos, SIRT1, and p16. Although knockdown of CARM1 or HuR individually influenced the expression of cyclin A, cyclin B1, c-fos, SIRT1, and p16, joint knockdown of both CARM1 and HuR did not show further effect. Methylation by CARM1 enhanced the association of HuR with the 3′UTR of p16 mRNA, but not with the 3′UTR of cyclin A, cyclin B1, c-fos, or SIRT1 mRNAs. In senescent human diploid fibroblasts (HDFs), reduced CARM1 was accompanied by reduced HuR methylation. In addition, knockdown of CARM1 or mutation of the major methylation site of HuR in HDF markedly impaired the ability of HuR to regulate the expression of cyclin A, cyclin B1, c-fos, SIRT1, and p16 as well to maintain a proliferative phenotype.

Conclusion

CARM1 represses replicative senescence by methylating HuR and thereby enhancing HuR’s ability to regulate the turnover of cyclin A, cyclin B1, c-fos, SIRT1, and p16 mRNAs.

Keywords:
CARM1; HuR methylation; mRNA turnover; Replicative senescence