Lewin Benjamin (ed.) Genes IX

This may explain the

presence

of some of the

noncoding

RNAs in

eukaryotic

nuclei;

they are

not regulator RNAs as such, but are the indi-

rect

products

of

a regulatory

system.

Bacteria

Contain

Regulator RNAs

a

BacteriaI regutator RNAs are catled sRNAs.

Several of the sRNAs are bound by the

protein

Hfq,

which increases their effectiveness.

The

OxyS

sRNA activates or represses expression of

>10

toci at

the

posttranscriptiona[

[eve[.

In bacteria,

regulator RNAs are short mole-

cules that are collectively

known

as

sRNAs;

E. coli contains at

least

seventeen different

sRNAs.

Some of the sRNAs are

general

regu-

lators that affect

many

target

genes.

They func-

tion by base

pairing

with target RNAs

(typically

mRNAs) to control either their stability

or

function.

An example of stability control

is

provided

by the

small antisense

regulator RyhB. which

regulates six

mRNAs coding for

proteins

con-

cerned

with

iron storage in E. coli.

RyhB base

pairs

with each of

the target mRNAs to form

double-stranded

regions

that are substrates

for

RNAase

E. An interesting feature of the circuit

is that the

ribonuclease destroys the regulator

RNA as well

as the mRNA.

Oxidative stress

provides

an interesting

example of

a

general

control system

in

which

RNA is the

regulator. When exposed to

reac-

tive

oxygen species, bacteria

respond by induc-

ing antioxidant

defense

genes.

Hydrogen

peroxide

activates the

transcription activator

OxyR, which

controls the expression of several

inducible

genes.

One of these

genes

is oxyS,

which codes

for a small RNA.

i::Ir-:i'i.

j

:r.:..r' shows two salient features of

the

control of oxyS expression.

In a wild-type

bacterium

under

normal

conditions,

it is

not

expressed.

The

pair

of

gels

on the left side

of the

figure show

that it

is

expressed

at high levels

in

a mutant bacterium

with a constitutively

active

oxyR

gene. This identifies oxyS as a target

for

activation

by oxyR

The

pair

of

gels

on the

right

side

of the

figure show that OxyS

RNA is tran-

scribed within

one minute of exposure

to hydro-

gen

peroxide.

The

OxyS RNA

is

a short

sequence

(109

nucleotides)

that does

not

code

for

protein. It

l':i;iiiil:

.i rr

.11

:-

The 5' untranstated

region of the

mRNA

for the

enzyme that synthesizes

GtcN6P

contains

a

ribozyme that

is actj-

vated by the

metabotic

product. The ribozyme

inactivates

the

mRNA by cteaving

it.

::'liii"liii:

li

;i.'i

r

Transcription

from an upstream

promoter

may

inhibit

initia-

tion at a

promoter

downstream

from

it, because

reading through

the down-

stream

promoter

prevents

the

necessary

transcription

factors

from binding

to

it. The RNA transcribed

from the

upstream

promoter

has no coding

function.

Regulatory

_I@-.

Turget

Promoter

Promoler

Initiation at

regulatory

promoter

reads through

target

promoter

13.8

Bacteria

Contain

Regulator

RNAs

347

Wtld- oxyR

type mutant

Add H2o2

oxyR

mRNA

*

oxyS

RNA

(109

nts)

t

Fl*LlRg

1i.:i

The

gets

on the

left show

that oxyS RNA

is induced

in

an oxyR

constitutive

mutant. The

qets

on

the

right

show that

oxyS RNA is induced

wjthin

one-minute

of

adding hydrogen

peroxide

to a wild-type

culture.

Repro-

duced from

Cell,

vol.90, Altuvia,

S.,

et at., A

small stable

RNA. .

.

,

pp.44-53.

Copyright

1997.

with

permission

from

Elsevier.

Photo

courtesy

of

Gisela Storz, National

Institutes

of Health.

flE*lJS*.

33-3*

oxyS RNA

inhibits

translation

oflhl

mRNA

by base

pairing

with

a sequence

just

upstream

of the AUG initiation

codon.

is

a trans-acting

regulator

that

affects

gene

expression

at

posttranscriptional

levels.

It has

>10

target

loci;

at some

of them,

it activates

expression;

at others

it represses

expression.

F?{:iJf;5

1;*1..i8

shows

the mechanism

of repres-

sion

of one

target,

the FlhA

mRNA.

Three

stem-

loop

structures

protrude

in

the secondary

structure

of OxyS

mRNA,

and the loop

close

to

the 3'terminus

is complementary

to a sequence

just

preceding

the initiation

codon

of

FIhA

mRNA.

Base

pairing

between

OxyS RNA

and

FlhA

RNA

prevents

the ribosome

from

binding

to the initiation

codon

and therefore

represses

translation. There is

also a second

pairing

inter-

action

that involves

a sequence

within the

cod-

ing

region

of FlhA.

Another

target for

oxyS is

rpoS, the

gene

coding for an

alternative sigma

factor

(which

activates a

general

stress response).

By inhibit-

ing

production

of the

sigma factor,

oxy.S

ensures

that the specific

response

to oxidative

stress

does

not trigger

the response

that is

appropriate

for

other stress

conditions. The

rpoS

gene

is also

regulated

by two other sRNAs

(DsrA

and RprA),

which

activate it. These

three

sRNAs

appear to

be

global

regulators

that coordinate

responses

to various

environmental

conditions.

The actions

of all

three sRNAs

are

assisted

by an RNA-binding protein

called

Hfq.

The Hfq

protein

was originally

identified

as

a bacterial

host

factor needed

for replication

of the RNA

bacteriophage

QB.

It is related

ro rhe

Sm

pro-

teins of eukaryotes

that

bind

to many

of the

snRNAs

(small

nuclear

RNAs)

that

have regu-

latory

roles in

gene

expression

(see

Section

26.5,

snRNAs

Are Required

for

Splicing).

Muta-

tions in its

gene

have

many

effects, which

iden-

tifies it

as a

pleiotropic

protein.

Hfq

binds

to

many

of the

sRNAs

of

E.

coli, and

it increases

the

effectiveness

of OxyS RNA

by

enhancing

its

ability

to bind

to irs rarget

mRNAs.

The

effect

of Hfq is

probably

mediated

by

causing

a small

change in

the secondary

structure

of OxyS RNA

that

improves

the

exposure

of the

single-

stranded

sequences

that

pair

with

the

target

mRNAs.

MicroRNAs

Are

Regulators

in

Many

Eukaryotes

.

Animal

and

ptant

genomes

code for

many

short

(-22

base) RNA

molecules

catted microRNAs.

r

MicroRNAs

regutate

gene

expression

by

base

pairing

with

complementary

sequences

in

target

mRNAs.

Very small

RNAs

are

gene

regulators

in

many

eukaryotes.

The first

example

was

discovered

in

the nematode

Caenorhabditis

elegans

as

the result

of the

interaction

between

the regulator gene

lin4 and

its target gene,

lin14. FIfrl"]ftgi

.t].r*

342

CHAPTER

13

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RNA

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25-JJ.

348

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