Tài liệu Báo cáo khoa học: Mixed lineage leukemia: a structure–function perspective of the MLL1

MINIREVIEW

Mixed lineage leukemia: a structure–function perspective

of the MLL1 protein

Michael S. Cosgrove and Anamika Patel

Department of Biology, Syracuse University, NY, USA

Introduction

Chromosomal translocations that disrupt the mixed

lineage leukemia protein-1 gene (MLL1, ALL1, HRX,

Htrx) are associated with a unique subset of acute

lymphoblastic or myelogenous leukemias [1–4]. The

product of the MLL1 gene is a large protein that func￾tions as a transcriptional co-activator required for the

maintenance of Hox gene expression patterns during

hematopoiesis and development [5–8]. The transcrip￾tional co-activator activity of MLL1 is mediated in

part by its histone H3 lysine 4 (H3K4) methyltransfer￾ase activity [6], an epigenetic mark correlated with

transcriptionally active forms of chromatin [9,10].

MLL1 complexes catalyze mono-, di- and trimethyla￾tion of H3K4, regulation of which can have distinct

functional consequences. MLL1 contains a number of

conserved functional domains that work together for

the assembly of multiprotein complexes that influence

the appropriate targeting and regulation of the H3K4

methylation activity of MLL1. In this minireview, we

summarize recent structural and functional studies that

are beginning to provide a picture of how these

domains are used to regulate the targeting, assembly

and enzymatic activity of MLL1 complexes.

The MLL protein

The MLL1 gene encodes a large protein of 3969 amino

acid residues that contains several conserved domains

with functions implicated in chromatin-mediated tran￾scriptional regulation [11] (Fig. 1). Domains include

DNA-binding AT hooks, a cysteine-rich CXXC

domain with homology to DNA methyltransferases,

plant homeodomain (PHD) finger motifs, a bromo

domain (BD), a transactivation domain (TAD), a

Keywords

Ash2L; CXXC; H3K4; methylation; MLL;

RbBP5; SET; TAD; WDR5; Win motif

Correspondence

M. S. Cosgrove, Syracuse University, 340

Life Sciences Complex, 107 College Place,

Syracuse, NY 13244, USA

Fax: +1 315 443 2012

Tel: +1 315 443 2964

E-mail: [email protected]

(Received 16 November 2009,

accepted 3 February 2010)

doi:10.1111/j.1742-4658.2010.07609.x

Several acute lymphoblastic and myelogenous leukemias are correlated with

alterations in the human mixed lineage leukemia protein-1 (MLL1) gene.

MLL1 is a member of the evolutionarily conserved SET1 family of histone

H3 lysine 4 (H3K4) methyltransferases, which are required for the regula￾tion of distinct groups of developmentally regulated genes in metazoans.

Despite the important biological role of SET1 family enzymes and their

involvement in human leukemias, relatively little is understood about how

these enzymes work. Here we review several recent structural and biochem￾ical studies that are beginning to shed light on the molecular mechanisms

for the regulation of H3K4 methylation by the human MLL1 enzyme.

Abbreviations

AdoHyc, S-adenosyl-homocysteine; BD, bromo domain; CBP, CREB-binding protein; CREB, cAMP response element-binding;

H3K4, histone H3 lysine 4; HMT, histone methyltransferase; MLL1, mixed lineage leukemia protein-1; PHD, plant homeodomain;

TAD, transactivation domain.

1832 FEBS Journal 277 (2010) 1832–1842 ª 2010 The Authors Journal compilation ª 2010 FEBS