TBP Loading by AF4 Through SL1 is the Major Rate-limiting Step in MLL Fusion-dependent Transcription

Overview

Journal Cell Cycle

Specialty Cell Biology

Date 2016 Aug 27

PMID 27564129

Citations 12

Authors

Hiroshi Okuda

Satoshi Takahashi

Akifumi Takaori-Kondo

Akihiko Yokoyama

Affiliations

Soon will be listed here.

Abstract

Gene rearrangement of the mixed lineage leukemia (MLL) gene causes leukemia by inducing the constitutive expression of a gene subset normally expressed only in the immature haematopoietic progenitor cells. MLL gene rearrangements often generate fusion products of MLL and a component of the AF4 family/ENL family/P-TEFb (AEP) complex. MLL-AEP fusion proteins have the potential of constitutively recruiting the P-TEFb elongation complex. Thus, it is hypothesized that relieving the promoter proximal pausing of RNA polymerase II is the rate-limiting step of MLL fusion-dependent transcription. AEP also has the potential to recruit the mediator complex via MED26. We recently showed that AEP activates transcription initiation by facilitating TBP loading to the TATA element through the SL1 complex. In the present study, we show that the key activity responsible for the oncogenic property of MLL-AEP fusion proteins is the TBP loading activity, and not the mediator recruitment or transcriptional elongation activities. Thus, we propose that TBP loading by AF4 through SL1 is the major rate-limiting step in MLL fusion-dependent transcription.

Citing Articles

RNA-binding proteins of KHDRBS and IGF2BP families control the oncogenic activity of MLL-AF4.

Okuda H, Miyamoto R, Takahashi S, Kawamura T, Ichikawa J, Harada I Nat Commun. 2022; 13(1):6688.

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The 3' Pol II pausing at replication-dependent histone genes is regulated by Mediator through Cajal bodies' association with histone locus bodies.

Suzuki H, Abe R, Shimada M, Hirose T, Hirose H, Noguchi K Nat Commun. 2022; 13(1):2905.

PMID: 35614107 PMC: 9133132. DOI: 10.1038/s41467-022-30632-w.

Leukemogenesis Model Using Retrovirus Transduction.

Okuda H, Yokoyama A Bio Protoc. 2021; 7(23):e2627.

PMID: 34595295 PMC: 8438401. DOI: 10.21769/BioProtoc.2627.

Myeloid Progenitor Transformation Assay.

Okuda H, Yokoyama A Bio Protoc. 2021; 7(23):e2626.

PMID: 34595294 PMC: 8438459. DOI: 10.21769/BioProtoc.2626.

HBO1-MLL interaction promotes AF4/ENL/P-TEFb-mediated leukemogenesis.

Takahashi S, Kanai A, Okuda H, Miyamoto R, Komata Y, Kawamura T Elife. 2021; 10.

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