LYAR potentiates rRNA synthesis by recruiting BRD2/4 and the MYST-type acetyltransferase KAT7 to rDNA.

Keiichi Izumikawa,Li Li,Harunori Yoshikawa,Hiroyuki Tachikawa,Toshiya Hayano,Toshiaki Isobe,Sally Fujiyama,Richard J Simpson,Akira Watanabe,Hideaki Ishikawa,Hiroyuki Aburatani,Yutaka Miura,Nobuhiro Takahashi,Jinrong Min

doi:10.1093/nar/gkz747

Abstract

Activation of ribosomal RNA (rRNA) synthesis is pivotal during cell growth and proliferation, but its aberrant upregulation may promote tumorigenesis. Here, we demonstrate that the candidate oncoprotein, LYAR, enhances ribosomal DNA (rDNA) transcription. Our data reveal that LYAR binds the histone-associated protein BRD2 without involvement of acetyl-lysine–binding bromodomains and recruits BRD2 to the rDNA promoter and transcribed regions via association with upstream binding factor. We show that BRD2 is required for the recruitment of the MYST-type acetyltransferase KAT7 to rDNA loci, resulting in enhanced local acetylation of histone H4. In addition, LYAR binds a complex of BRD4 and KAT7, which is then recruited to rDNA independently of the BRD2-KAT7 complex to accelerate the local acetylation of both H4 and H3. BRD2 also helps recruit BRD4 to rDNA. By contrast, LYAR has no effect on rDNA methylation or the binding of RNA polymerase I subunits to rDNA. These data suggest that LYAR promotes the association of the BRD2-KAT7 and BRD4-KAT7 complexes with transcription-competent rDNA loci but not to transcriptionally silent rDNA loci, thereby increasing rRNA synthesis by altering the local acetylation status of histone H3 and H4.

Highlights

The ribosome is the essential cellular machinery for protein synthesis
Given that LYAR overexpression does not affect the cellular levels of MYC, PTEN, retinoblastoma, and p53 [20], we hypothesized that LYAR promotes ribosomal DNA (rDNA) transcription via a pathway independent of those proteins, we could not exclude the possibility that LYARinduced proteins other than those listed above may be involved in rDNA transcription
Among several transcription regulatory factors that associate with LYAR (Table 1), we identified BRD2, KAT7, and BRD4 as being recruited by LYAR to rDNA

Summary

Introduction

The ribosome is the essential cellular machinery for protein synthesis. The eukaryotic ribosome consists of a large 60S subunit and a small 40S subunit, the biogenesis of which requires transcription of a large ribosomal RNA precursor (47S pre-rRNA) by RNA polymerase (RNAP) I, a 5S rRNA by RNAP III, and translation of ribosomal proteins from mRNAs transcribed by RNAP II [1,2,3,4,5,6]. Numerous small nucleolar RNAs and nonribosomal proteins (called trans-acting factors) participate in ribosome biogenesis [5,6]. Among these factors, many contribute to the synthesis of 47S pre-rRNA, which alone constitutes ∼80% of the total transcription of proliferating cells [1,2].

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Conclusion