MCAF1/AM Is Involved in Sp1-mediated Maintenance of Cancer-associated Telomerase Activity

Lifeng Liu,Ko Ishihara,Takaya Ichimura,Naoyuki Fujita,Shinjiro Hino,Saori Tomita,Sugiko Watanabe,Noriko Saitoh,Takaaki Ito,Mitsuyoshi Nakao

doi:10.1074/jbc.m807098200

Abstract

Telomerase maintains telomere length and is implicated in senescence and immortalization of mammalian cells. Two essential components for this enzyme are telomerase reverse transcriptase (TERT) and the telomerase RNA component (encoded by the TERC gene). These telomerase subunit genes are known to be mainly expressed by specificity protein 1 (Sp1). MBD1-containing chromatin-associated factor 1 (MCAF1), also known as ATFa-associated modulator (AM) and activating transcription factor 7-interacting protein (ATF7IP), mediates gene regulation, although the precise function of MCAF1 remains to be elucidated. Here, we report that MCAF1 is involved in Sp1-dependent maintenance of telomerase activity in cancer cells. Two evolutionarily conserved domains of MCAF1 directly interact with Sp1 and the general transcriptional apparatus. Selective depletion of MCAF1 or Sp1 down-regulates TERT and TERC genes in cultured cells, which results in decreased telomerase activity. The transcriptionally active form of RNA polymerase II and the general transcription factor ERCC3 decreased in the TERT promoter under the loss of MCAF1 or Sp1. Consistently, MCAF1 is found to be frequently overexpressed in naturally occurring cancers that originate in different tissues. Our data suggest that transcriptional function of MCAF1 facilitates telomerase expression by Sp1, which may be a common mechanism in proliferative cancer cells.

Highlights

Risk of genetic and epigenetic defects [7]
The telomerase enzyme consists of two essential components, telomerase reverse transcriptase (TERT)2 and the telomerase RNA component (TR; encoded by the TERC gene), which serves as a template for telomeric DNA synthesis
We initially found that methylated DNA-binding domain protein 1 (MBD1) interacts with MBD1-containing chromatin-associated factor 1 (MCAF1) [17], known as ATFaassociated modulator (AM) and activating transcription factor 7-interacting protein (ATF7IP) [18]

Summary

Introduction

Risk of genetic and epigenetic defects [7]. The telomerase enzyme consists of two essential components, telomerase reverse transcriptase (TERT)2 (encoded by the TERT gene) and the telomerase RNA component (TR; encoded by the TERC gene), which serves as a template for telomeric DNA synthesis. MCAF1-Sp1 Complex Is Involved in Maintaining the Localization of Phosphorylated RNA Polymerase II and General Transcription Factor in the TERT Promoter—To examine transcriptional control by the MCAF1-Sp1 complex, we analyzed the status of modified histones in the TERT promoter, by a quantitative ChIP analysis using specific antibodies (supplemental Fig. S4).

Results

Conclusion