Lewin Benjamin (ed.) Genes IX

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@

Introduction

Gene

expression can be controlled

at any of sev-

eral stages, which we divide

broadly

into

tran-

scription.

processing,

and translation:

.

Tianscription

often is

controlled at the

stage

of

initiation.

Tlanscription is not

usually controlled at

elongation. but

may

be controlled

at termination to

determine

whether RNA

polymerase

is

allowed to

proceed

past

a terminator to

the

gene(s)

beyond.

.

In

eukaryotic cells,

processing

of the

RNA

product

may be regulated

at the

stages of modification,

splicing, trans-

port,

or stability. In bacteria,

an

mRNA

is in

principle

available

for translation

as

soon as

(or

even while) it is

being

synthesized, but during

this time the

stages of control

are not available.

.

Translation

may be regulated,

usually

at the stages of initiation

and termina-

tion

(like

transcription).

Regulation of

initiation

is formally

analogous to the

regulation

of transcription:

the circuitry

can be drawn in

similar terms for

regu-

lating initiation

of transcription

on DNA

or initiation

of translation

on

RNA.

The

basic concept for how

transcription is

controlled in

bacteria

was

provided

by

the clas-

sic formulation

of

the

model

for control

of

gene

expression

by

Jacob and Monod in

1961. They

distinguished

between two

types of sequences

in DNA:

sequences that

code for trans-acting

products

and

crs-acting sequences

that func-

tion exclusively

within the DNA.

Gene activity

is regulated

by the

specific interactions

of the

trans-acting

products

(usually proteins)

with

the cls-acting

sequences

(usually

sites in DNA).

In more

formal

terms:

f

ii:,

1

j

i'tLr i ir. i,

A regutator

gene

codes

for

a

protein

that acts

at

a target

site on DNA.

CHAPTER

12 The

0peron

.

A

gene

is a sequence

of

DNA

that codes

for a diffusible

product.

This

product

may

be

protein (as

in the case

of the

majority of

genes)

or may

be RNA

(as

in

the case

of

genes

that code for

IRNA and

rRNA). The crucial

feature

is

that the

prod-

uct dffises away

from

its

site of synthesis

to

act

elsewhere.

Any

gene

product

that is

free to diffuse to find its

target is

described

as

tr

ans

-

acting.

.

The description cls-acting

applies to any

sequence

of

DNA

that is not

converted

into

any other form, but

that functions

exclusively as a DNA

sequence in situ,

affecting

only the

DNA

to which it is

physically

linked.

(In

some cases, a crs-

acting

sequence functions in

an RNA

rather than in a DNA

molecule.)

To help distinguish

between the components

of regulatory

circuits and the

genes

that they reg-

ulate, we sometimes use the

terms structural

gene

and

regulator

gene.

A structural

gene

is

simply any

gene

that

codes

for

a

protein

(or

RNA)

product.

Structural

genes

represent

an enormous

variety

of

protein

structures

and functions,

including

structural

proteins,

enzymes

with cat-

alytic activities,

and

regulatory

proteins.

A reg-

ulator

gene

simply describes

a

gene

that codes

for

a

protein (or

an RNA) involved

in regulating

the expression of other

genes.

The simplest form

of the regulatory

model

is illustrated in Ft{:*&$.

't'l.ii

a regulator

gene

codes

for

a

protein

that controls transcription

by binding

to

particular

site(s)

on

DNA.

This interaction

can

regulate

alargel

gene

in either

a

positive

man-

ner

(the

interaction turns

the

gene

on) or in a

negative manner

(the

interaction

turns the

gene

off). The sites on DNA

are usually

(but

not exclu-

sively) located

just

upstream

of the target

gene.

The sequences

that mark the

beginning

and

end

of the transcription

unit, the

promoter

and

terminator, are

examples of cls-acting

sites. 4

prlmlter

serves

to initiate transcription

only

of the

gene

0r

genes physically

connected

to it on the

same

stretch

of

DNA.

In the same

way, a

terminator

can terminate

transcription

only

by an RNA

polymerase

that has

traversed

the

preceding

gene(s).

In their

simplest forms,

promoters

and

terminators

are cls-acting

elements

that are rec-

ognized by the

same trans-actingspecies,

that is,

by RNA

polymerase (although

other factors

also

participate

at each

site).

Additional

cls-acting regulatory

sites

are often

juxtaposed

to,

or

interspersed

with,

the

promoter.

A bacterial

promoter

may have

one

or more such

sites located

close by, that is, in

the immediate

Regulator

gene

I

v

mRNA

I

v

..i:i

Regulator

protein

+

Target

site

Structural

gene

302

vicinity of the startpoint. A

eukaryotic

promoter

is likely to have

a

greater

number

of sites

that

are

spread out over a longer

distance.

Regulation

Can Be

Negative

or

Positive

In negative regulation,

a

repressor

protein

binds

to an operator to

prevent

a

gene

from

being

expresseo.

In

positive

regulation,

a transcription factor is

required

to bjnd at the

promoter

in order

to enable

RNA

potymerase

to initiate

transcription.

A

classic

mode

of control in

bacteria is negative:

a repressor

protein

prevents

a

gene

from

being

expressed.

i:i+ijiii;

: ll

,;:

shows

that the

"default

state"

for

such a

gene

is to

be expressed via the

recognition

of its

promoterby

RNApolymerase.

CIose to the

promoter

is

another cli-acting

site

called the operator, which is

the target for the

repressor

protein.

When the repressor

binds to

the operator, RNA

polymerase

is

prevented

from

initiating transcription

and

gene

expression

is there-

fore

turned off.

An alternative mode

of control is

positive.

This is

used

in

bacteria

(probably)

with about

equal frequency to negative

control, and it is

the most

common mode of control

in eukary-

otes.

A

transcription factor is required

to assist

RNA

polymerase

in initiating

at the

promoter.

i::i{:ijiirl 1

;:,.ri

shows that the typical

default state

of a eukaryotic

gene

is inactive:

RNA

polymerase

cannot by

itself

initiate transcription

at the

pro-

moter. Several trans-acling

factors have

target

sites in the vicinity

of the

promoter,

and bind-

ing of some or all of these

factors

enables RNA

poly-

merase to initiate transcription.

The unifying theme is

that

regulatory

pro-

teins are trans-acting factors

that recognize

cls-

acting elements

(usually)

upstream

of the

gene.

The

consequences of this recognition

are to acti-

vate or to repress the

gene,

depending on the

individual type

of

regulatory

protein.

A typical

feature is that the

protein

functions

by recog-

nizing a

very

short sequence in DNA, usually

<10

bp

in length,

although the

protein

actually

binds over a somewhat

greater

distance of DNA.

The

bacterial

promoter

is

an example: RNA

poly-

merase covers

>70

bp of DNA at initiation,

but

the crucial sequences that it recognizes

are the

hexamers centered at

-35

and

-I0.

A significant difference in

gene

organiza-

tion between

prokaryotes

and

eukaryotes

is

that

rir.;i,lFili. t::r.;:

In

negative controt, a frons-acting

repressor

binds to the crs-acting

operator to turn

off transcription.

frlt

i.iiiii

l;l.ri In

positive

controt,

trans-acting

factors

must

bind to crs-acting sites

in order

for RNA

potymerase

to

ini-

tiate transcription at

the

promoter.

structural

genes in bacteria

are organized

in

clusters.

whereas those

in eukaryotes

occur

indi-

vidually. Clustering

of structural

genes

allows

them to be coordinately

controlled

by means

of interactions

at a single

promoter: as a

result

of these

interactions,

the entire

set of

genes

is

either transcribed

or

not transcribed.

In this

cr+acting operator/promoter

precedes

structural

gene(s)

Promoter Operator

Structural

gene(s)

Gene on: RNA

polymerase

initiates at

promoter

RNA

i,

,

l'',,

ln,

'

:1,

.,r"'r-..,

j'r'

...,"'

I

erotein

6ffiffi

Gene

is

turned off

when repressor

binds to operalor

Repressor

I

GENE TURNED

ON BYACTI

ORS

Factors interact with

RNA

polymerase

RNA

I

v

12.2

Regutation

Can

Be Negative

or Positive 303

chapter, we discuss this mode of control and its

use by bacteria. The means employed to coor-

dinate control

of dispersed eukaryotic

genes

are

discussed in

Chapter

25, Activating

Tfanscription.

and

galactose (which

are then further

metabolized). This enzyme

also

produces

an important

by-product,

p-1,

6-allo-

lactase,

which

has

a role in regulation.

.

lacY

codes

for

the

p-galactoside

perme-

ase, a l0-kD membrane-bound

protein

constituent of the transport system. This

transports

B-galactosides

into

the cell.

.

lacA codes for

B-galactoside

transacety-

lase, an enzyme that transfers

an acetyl

group

from

acetyl-CoA to

B-galactosides.

Mutations in either lacZ or lacY

can create

the lac

genolype,

in

which cells cannot utilize lac-

tose.

(The genotlpic

description

"lac"

withoul a

qualifier

indicates loss-of-funclion.\

Ti;re lacZ

mutations

abolish enzyme activity, directly

pre-

venting

metabolism

of lactose. The /acYmutants

cannot take up lactose from

the medium.

(No

defect

is

identifiable in lacA cells,

which

is

puzding.

It is

possible

that the acetylation reaction

gives

an advantage when the bacteria

grow

in

the

pres-

ence of certain analogs of

B-galactosides

that can-

not be metabolized,

because the modification

results in

detoxification and excretion.)

The

entire system,

including

structural

genes

and the elements that control

their expres-

sion, forms a

common unit of regulation

called

an operon. The

activity of the operon is

con-

trolled by

regulator

gene(s)

whose

protein prod-

ucts

interact

with the as-acting

control elements.

The

lqc Genes

Are

Contro[Led by a

Repressor

Transcription of

the

lacZYA

gene

cluster is

controlled by a repressor

protein

that binds to an

operator

that overlaps the

promoter

at the start of

the ctuster.

The

repressor

protein

is a

tetramer of identical

subunits coded by the

gene

lacf.

;:.:{ii"!i:i,,r

.1 ..r.,,, The

lacoperon

occupies

-6000

bp of DNA. Atthe

Leftthe laclgene has its

own

pro-

moter

and

terminator. The

end of the locl region is

adjacent to the

promoter,

P. The

operator,

0

occupies the first 26

bp of the transcription

unit. The long IacZ

gene

starts at base 39, and is fot-

lowed

bv the LacY and lac,4

qenes

and a terminator.

@

Structural Gene

Clusters

Are

CoordinateLy

ControLLed

r

Genes coding for

proteins

that

function in

the

same

pathway

may

be [ocated adjacent to one

another and

controlted as a singte unit that

is

transcribed into

a

polycistronic

mRNA.

Bacterial

structural

genes

are often organized

into

clusters that include

genes

coding

for

pro-

teins whose functions

are related. It is common

for

the

genes

coding for the

enzymes of a meta-

bolic

pathway

to be organized into such a clus-

ter. In

addition to the enzymes actually involved

in

the

pathway,

other related

activities

may

be

included

in the

unit of coordinate control; for

example,

the

protein

responsible for

transport-

ing

the small molecule

substrate into the cell.

The

cluster of the three lac

structural

genes,

lacZYA,

is typical.

'i,rlj:ri.

i..lr'i.

gsppurizes

the

organization of the

structural

genes,

their asso-

ciated cli-acting regulatory

elements, and the

trans-acting regulatory

gene.

The key

feature

is

that

the cluster is transcribed

into a single

polycistrontc

wRNA

from

a

promoter

where initiation

of

transcrip-

tion is regulated.

The

protein products

enable

cells to take

up and

metabolize

B-galactosides,

such as lac-

tose. The roles

of the three structural

genes

are:

.

lacZ codes for

the enzyme

B-galactosi-

dase,

whose

active form is a tetramer

of

-500

kD. The

enzyme breaks a

B-galac-

toside into its

component

sugars.

For

example, lactose

is cleaved into

glucose

304

CHAPTER 12 The

0peron

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