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Along the Central Dogma--Controlling Gene Expression with Small Molecules

Article in Annual Review of Biochemistry ? June 2018

DOI: 10.1146/annurev-biochem-060614-033923

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Annual Review of Biochemistry

Along the Central Dogma--Controlling Gene Expression with Small Molecules

Tilman Schneider-Poetsch1 and Minoru Yoshida1,2

1Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Saitama 351-0198, Japan; email: yoshidam@riken.jp 2Department of Biotechnology, University of Tokyo, Tokyo 113-8657, Japan

Annu. Rev. Biochem. 2018.87:391-420. Downloaded from Access provided by Riken Institute - Wako Campus on 10/11/18. For personal use only.

Annu. Rev. Biochem. 2018. 87:391?420

First published as a Review in Advance on May 4, 2018

The Annual Review of Biochemistry is online at biochem.

biochem060614- 033923

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Keywords

chemical biology, gene expression, natural products, transcription, translation, RNA metabolism

Abstract

The central dogma of molecular biology, that DNA is transcribed into RNA and RNA translated into protein, was coined in the early days of modern biology. Back in the 1950s and 1960s, bacterial genetics first opened the way toward understanding life as the genetically encoded interaction of macromolecules. As molecular biology progressed and our knowledge of gene control deepened, it became increasingly clear that expression relied on many more levels of regulation. In the process of dissecting mechanisms of gene expression, specific small-molecule inhibitors played an important role and became valuable tools of investigation. Small molecules offer significant advantages over genetic tools, as they allow inhibiting a process at any desired time point, whereas mutating or altering the gene of an important regulator would likely result in a dead organism. With the advent of modern sequencing technology, it has become possible to monitor global cellular effects of small-molecule treatment and thereby overcome the limitations of classical biochemistry, which usually looks at a biological system in isolation. This review focuses on several molecules, especially natural products, that have played an important role in dissecting gene expression and have opened up new fields of investigation as well as clinical venues for disease treatment.

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Annu. Rev. Biochem. 2018.87:391-420. Downloaded from Access provided by Riken Institute - Wako Campus on 10/11/18. For personal use only.

Contents

INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 392 TRANSCRIPTION INHIBITORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395 EPIGENETIC INHIBITORS: DNA METHYLATION . . . . . . . . . . . . . . . . . . . . . . . . . . . 400 EPIGENETIC INHIBITORS: HISTONE MODIFIERS . . . . . . . . . . . . . . . . . . . . . . . . . . 400 READER INHIBITORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403 HISTONE METHYLTRANSFERASE INHIBITORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404 SPLICING INHIBITORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404 NUCLEAR EXPORT INHIBITORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408 NONSENSE-MEDIATED mRNA DECAY INHIBITORS . . . . . . . . . . . . . . . . . . . . . . . . 409 TRANSLATION INHIBITORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409

INTRODUCTION

To this day, plant and microbial metabolites constitute a major source of medicinal drugs as well as biological probes for research use (1, 2). The utilization of natural products for medical and recreational purposes dates back tens of thousands of years and, despite ever more sophisticated synthetic methodology, continues to this day. The likelihood of finding an active molecule in a library of natural products is usually much higher than the chance of finding an equally effective compound in a purely synthetic collection (3, 4). As the high hopes put in large combinatorial libraries of synthetically produced molecules remain unfulfilled, as they have yielded only a small number of active compounds, the use of naturally occurring molecular scaffolds as the basis for synthesis is increasingly garnering interest (5). We focus on natural products in our discussion of molecules that inhibit or modulate gene expression (Table 1), although we also mention synthetic compounds when appropriate. Hence, we also do not discuss molecules that affect transcription via signal transduction, such as inhibitors of JAK/Stat or mammalian target of rapamycin (mTOR) signaling pathways.

At the core of molecular biology lies DNA as information storage, which is then copied into RNA to produce a template for protein synthesis (Figure 1). Hence, it seemed that three macromolecules and the processes of transcription and translation could explain most of life itself and that there was not much left to discover (6). Fortunately, such pessimistic thought did not prevail and it became clear that life at a molecular level was not only more fascinating but also much more complicated than originally anticipated. While molecular biology originally concerned itself primarily with the manipulation of DNA, RNA started to take on an increasingly central role in the view of life. In some cases, the direction postulated by the central dogma may be reversed, as in several families of RNA viruses that force their host to produce DNA "hard copies" of their genomes, whereas others function just with RNA genomes and omit the DNA stage altogether (7). Furthermore, in eukaryotes especially, a series of many processes lies between transcription and protein production, which in many stages involves RNA regulators. To produce usable protein, the nascent messenger RNA (mRNA) receives a cap and a poly-A tail. Additionally, it is spliced, checked for premature stop codons, and finally exported. Even then, small silencing RNAs may command destruction of the final transcript or alter its expression level via microRNAs before the mRNA actually reaches the ribosome (8). Although one could still claim that these events are more or less details following the outline of the central dogma, the expression and organization of the genes themselves depend on epigenetic regulators, whose information content is passed on

? 392 Schneider-Poetsch Yoshida

Annu. Rev. Biochem. 2018.87:391-420. Downloaded from Access provided by Riken Institute - Wako Campus on 10/11/18. For personal use only.

Table 1 List of molecules targeting mechanisms of gene expression

Name Parthenolide Actinomycin D

-Amanitin Flavopiridol

DRB Triptolide 5-Azacytidine Decitabene Zebularine SGI-1027 Trichostatin A SAHA Trapoxin B Apicidin Chlamydocin

CHAP 31 FK228 HC-toxin Sirtinol Splitomicin EX-527 SirReal2 Suramin

Garcinol Curcumin Anacardic acid C646 Chaetocin

BIX-01294 UNC0638 GSK126

EPZ-6348

PubChem ID

7251185 2019

73755106 5287969

5894 107985 9444 451668 100016 24858111 444732 5311 395803 6918328 124134

56603758 5352062 107864 5717148 5269 5113032 1096292 5361

174159 969516 167551 1285941 11657687

25150857 46224516 68210102

66558664

Type Plant natural product Bacterial natural product

Fungal natural product Semisynthetic

Synthetic Plant natural product Synthetic Synthetic Synthetic Synthetic Bacterial natural product Synthetic Fungal natural product Fungal natural product Fungal natural product

Synthetic Bacterial natural product Fungal natural product Synthetic Synthetic Synthetic Synthetic Synthetic

Plant natural product Plant natural product Plant natural product Synthetic Fungal natural product

Synthetic Synthetic Synthetic

Synthetic

Origin Tanacetum parthenium Streptomyces parvulus

Amanita phalloides Derivative of rohitukine

from Aphanamixis polystachya NA Tripterygium wilfordii NA NA NA NA Streptomyces spp. NA Helicoma ambiens Fusarium spp. Diheterospora chlamydosporia NA Chromobacterium violaceum Cochliobolus carbonum NA NA NA NA NA

Garcinia indica Curcuma longa Ginkgo biloba NA Chaetomium minutum

NA NA NA

NA

Target NF-B pathway RNA synthesis

RNA polymerase II Cdk9

Cdk9 XPB subunit of TFIIH DNA methyltransferase DNA methyltransferase DNA methyltransferase DNA methyltransferase Histone deacetylase Histone deacetylase Histone deacetylase Histone deacetylase Histone deacetylase

Histone deacetylase Histone deacetylase Histone deacetylase Sirtuins Sirtuins SIRT1 SIRT2 Sirtuins

Histone acetyltransferases Histone acetyltransferases Histone acetyltransferases CBP/p300 Histone methyltransferases G9a G9a EZH

EZH

Use(s) Bioprobe Therapeutic

and bioprobe Bioprobe Experimental

therapeutic

Bioprobe Therapeutic Therapeutic Therapeutic Therapeutic Bioprobe Bioprobe Therapeutic Bioprobe Bioprobe Bioprobe

Bioprobe Therapeutic Bioprobe Bioprobe Bioprobe Bioprobe Bioprobe Therapeutic

(unrelated application) Bioprobe Bioprobe Bioprobe Bioprobe Bioprobe

Bioprobe Bioprobe Experimental

therapeutic Experimental

therapeutic (Continued)

? Controlling Gene Expression with Small Molecules 393

Annu. Rev. Biochem. 2018.87:391-420. Downloaded from Access provided by Riken Institute - Wako Campus on 10/11/18. For personal use only.

Table 1 (Continued)

Name EPZ-5676

PubChem ID

57345410

Type Synthetic

JQ1 I-BET

46907787 46943432

Synthetic Synthetic

Origin NA

NA NA

Target DOT1L

Bromodomains Bromodomains

Spliceostatin A 10673568

Pladienolide Isoginkgetin E7107

16202130 5318569 16202132

Semisynthetic

Bacterial natural product Plant natural product Synthetic

Derivative of FR901464 from Pseudomonas spp. Streptomyces platensis Ginkgo biloba NA

Spliceosome

Spliceosome Spliceosome Spliceosome

TG003

1893668 Synthetic

NA

NVS-SM1

86710591 Synthetic

NA

Leptomycin B KPT-330

57459335 71481097

Bacterial natural product Streptomyces spp.

Synthetic

NA

Clk U1snRNP and SMN2 mRNA Exportin 1 Exportin 1

NMD I

12733992 Synthetic

NA

Pateamine A Hippuristanol Rocaglamide Allolaurinterol Elisabatin A

10053416 9981822 331783 470278 397069

Reveromycin A 9939559

Febrifugine

63224

Marine natural product Marine natural product Plant natural product Marine natural product Marine natural product

Bacterial natural product Plant natural product

Mycale hentscheli Isis hippuris Aglaia elliptifolia Laurencia filiformis Pseudopterogorgia elisabethae Streptomyces spp. Dichroa febrifuga

Nonsense-mediated RNA decay eIF4A eIF4A eIF4A eIF4A eIF4A

Ile tRNA synthetase Glu Pro tRNA synthetase

AN2690

11499245

Homoharringtonine

285033

Cytotrienin

11966097

Agelastatin A 177936

Lycorine

72378

Narciclasine 72376

Cycloheximide 6197

Lactimidomycin 11669726

Mycalamide A 10345974

Synthetic Plant natural product

NA

Leu tRNA synthetase

Cephalotaxus harringtonia Ribosome

Bacterial natural product Marine natural product Plant natural product Plant natural product Bacterial natural product Bacterial natural product Marine natural product

Streptomyces spp.

tRNA binding

Agelas dendromorpha

Ribosome

Clivia miniata

Ribosome

Narcissus spp.

Ribosome

Streptomyces griseus

Ribosome

Streptomyces amphibiosporus Ribosome

Mycale spp.

Ribosome

Use(s) Experimental

therapeutic Bioprobe Bioprobe and

experimental therapeutic Bioprobe

Bioprobe Bioprobe Experimental

therapeutic Bioprobe Experimental

therapeutic Bioprobe Experimental

therapeutic Bioprobe

Bioprobe Bioprobe Bioprobe Bioprobe Bioprobe

Bioprobe Bioprobe and

experimental therapeutic Therapeutic Therapeutic

Bioprobe Bioprobe Bioprobe Bioprobe Bioprobe Bioprobe Bioprobe

Abbreviations: Cdk9, cyclin-dependent kinase 9; NA, not applicable; NF-B, nuclear factor B; TFIIH, transcription factor IIH ; tRNA, transfer RNA; XPB, xeroderma pigmentosum type B.

? 394 Schneider-Poetsch Yoshida

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