Lewin Benjamin (ed.) Genes IX

We shall

not at this

point

deal

in

detail with

the other

functions needed to establish lysogeny,

but we can

just

briefly remark that the infect-

ing

lambda DNA must be inserted into the

bac-

terial

genome (see

Section 19.I7, Specialized

Recombination Involves Specific Sites). The

insertion requires the

product

of

gene

int,which

is expressed

from its

own

promoter

{,

at which

cII also

is necessary. The

sequence of

P, shows

homology

with

P*" in the cII binding site

(although

not in the

-10

region). The functions

necessary for establishing the lysogenic control

circuit are therefore under the same control

as

the

function needed to integrate the

phage

DNA

into the bacterial

genome.

Thus

the establish-

ment of

lysogeny is under a control that ensures

all the necessary events occur with the

same

timing.

Emphasizing

the tricky

quality

of lambda's

intricate cascade. we

now know

that

cII

pro-

motes

lysogeny in another, indirect manner. It

sponsors

transcription from a

promoter

called

Pu,ti-q, which

is located within the

Q

gene.

This

transcript is an antisense version of the

Q

region,

and

it hybridizes with

Q

mRNA to

prevent

trans-

lation of

Q

protein, whose

synthesis is essen-

tial

for lytic development. Thus the same

mechanisms that directly

promote

lysogeny by

causing

transcription of the cI

repressor

gene

also

indirectly help lysogeny by inhibiting the

expression of

cro

(see

above) and

Q,

the regu-

lator

genes

needed for the antagonistic

lytic

nathwav.

The

cro Repressor

Is Needed

for Lytic

Infection

.

Cro

binds to the same operators as

repressor. but

with different affi

nities.

.

When

Cro binds to 003,

it

prevents

RNA

potymerase

from

binding

to P*.,, and blocks

maintenance

of

reDreSs0r.

.

When Cro binds

to other operators at 0* or 0r,

it

prevents

RNA

potymerase

from

expressing

immediate earty

genes,

which

(indirectty)

bl.ocks

reDressor estabtishment.

Lambda

has the altematives of entering

lysogeny

or

starting a

lytic infection. Lysogeny

is initi-

ated by

establishing an autogenous

mainte-

nance circuit that

inhibits the entire lytic cascade

through

applying

pressure

at

two

points.

The

program

for establishing

lysogeny

proceeds

through

some of

the same

events

that

are

required for the

lytic

cascade

(expression

of

delayed early

genes

via

expression

of

N is

needed). We now

face a

problem.

How

does the

phage

enter

the

lytic cycle?

The key

influence

on the

lytic cycle

is the

role of

gene

cro,

which codes

for another

repres-

sor.

Cro is responsible

for

preventing the synthesis

of

the repressor

protein;Ihis

action

shuts off

the

pos-

sibility of establishing

lysogeny.

cro

mutants

usu-

ally establish

lysogeny

rather

than entering

the

lytic

pathway,

because

they

lack the ability

to

switch events

away

from

the expression

of

repressor.

Cro forms

a small

dimer

(the

subunit

is

9 kD) that acts within

the

immunity

region.It

has two effects:

.

It

prevents

the

synthesis

of

repressor

via

the maintenance

circuit;

that

is, it

pre-

vents

transcriPtion

via P**.

.

It also

inhibits

the expression

of early

genes

from

both

Pr and

P*.

This means

that, when

a

phage

enters the

lytic

pathway,

Cro

has

responsibility

both

for

preventing

the

synthesis

of

repressor

and

(sub-

sequently)

for turning

down

the expression

of

the early

genes.

Cro

achieves

its

function

by binding

to

the

same operators

as

(cI)

repressor

protein'

Cro

includes a

region with

the

same

general struc-

ture

as the repressor;

a

helix-2

is offset

at an

angle from

recognition

helix-1.

(The

remain-

der of the structure

is different,

which

demon-

strates

that

the

helix-turn-helix

motif can

operate

within

various contexts.)

As for

repres-

sor. Cro

binds symmetrically

at the

operators.

The sequences

of

Cro and

repressor

in the

helix-turn-helix

region

are

related,

which

explains

their ability

to contact

the

same

DNA

sequences

(see

Figure

I4.2I\.

Cro

makes sim-

ilar contacts

to those

made

by

repressor,

but

binds

to only

one

face of

DNA;

it

lacks the N-

terminal

arms

by

which

repressor

reaches

around to

the other

side.

How can

two

proteins have

the same

sites

of action,

yet

have such

opposite

effects?

The

answer

lies

in the different

affinities

that each

protein

has

for the

individual

binding

sites

within

the operators.

Let us

just

consider

O*,

for which

more

is known,

and where

Cro

exerts

both its effects.

The

series

of events

is illustrated

in

F3fr{Jsf,

x'i.3}.

(Note

that

the

first

two stages

are

identical

to those

of the

lysogenic

circuit

shown

in Figure

14.32.)

The affinity

of

Cro

for

O*3

is

greater

than

its affinity

for O*2

or

O*1.

Thus

it binds

first to

74.20

Ihe cro

Repressor

Is

Needed

for Lytic

Infection

377

N antiterminates;

cll and

clll

are transcribed

EXPRESSION

cll

Pe,

Cto rePresses

c/

"

and all

earlv

FIGU*E

14.33 The

lytic

cascade requires

Cro

protein,

which

directty

prevents

repressor

maintenance

via

P*r,

as wetl as

turning

off delayed

early

gene

expression, indirectLy

preventing

repressor

estab-

[ishment.

O*3.

This inhibits

RNA

polymerase

from

bind-

ing

to P"*.

As

a result,

Cro's

first

action is

to

prevent

the

maintenance

circuit

for lysogeny

from

coming

into

play.

Cro

then

binds to

O*2 or

O*1. Its

affiniry

for

these

sites is

similar,

and

there is no

coop-

:,H'L'""ff:1il

iliil:ffi?ifJ

n:"J,,

*"

P*.

This

in turn

stops

the

production

of the

early

lunctions (including

Cro itself).

As

a

result

of

cII's

instability,

any use

of

p*,

is

brought

to a

CHAPTER

14 Phage

Strategies

halt. Thus

the two

actions

of Cro together

block

a/i

production

of repressor.

As far

as the lytic

cycle is

concerned,

Cro

turns

down

(although

it

does not

completely

eliminate)

the

expression

of the

early

genes.

Its

incomplete

effect is

explained

by its

affinity

for

O*l and

O*2, which

is about

eight

times

lower

than

that

of repressor.

This

effect

of Cro

does

not

occur

until

the early

genes

have

become

more

or less

superfluous,

because pe

is

pres-

ent;

by this

time, the

phage

has started

late

gene

372

expression and

is

concentrating on the

produc-

tion of

progeny phage particles.

What

Determines

the

Balance Between

Lysogeny and the

Lytic

Cycle?

The delayed early stage

when

both Cro and

repressor are being expressed

is

common to

lysogeny

and the lytic cycte.

The

criticaI

event is whether cII causes sufficient

synthesis

of repressor to overcome the action

of Cro.

The

programs

for the lysogenic and lytic

path-

ways are so intimately

it is impos-

sible to

predict

the fate of an individual

phage

genome

when

it

enters a

new host bacterium.

Will the

antagonism between repressor and Cro

be resolved by establishing

the autogenous

maintenance circuit shown in Figure

14.32, or

by turning

off repressor synthesis and entering

the late stage of development

shown in

Figure

14.33?

The same

pathway

is followed in both cases

right up to

the brink of decision. Both

involve

the

expression of the

immediate early

genes

and extension

into the delayed early

genes.

The

difference between

them comes down to the

question

of whether repressor or Cro

will obtain

occupancy

of the

two operators.

The early

phase

during which the

decision

is made

is limited in duration in either case. No

matter which

pathway

the

phage follows,

expression

of all early

genes

will be

prevented

as P. and P* are

repressed and, as a consequence

of the disappearance

of cII and cIII,

production

of

repressor via

P*u

will cease.

The

critical

question

comes

down to

whether the

cessation of transcription

from P*.

is followed by activation

of P** and the estab-

lishment

of lysogeny, or

whether P** fails to

become active

and the

pQ

regulator commits

the

phage

to lytic development.

:rJ{rl"iiitrr" :.'rr,

{l

shows the

critical stage, at which

both repres-

sor

and Cro are

being synthesized.

The initial event

in

establishing

lysogeny

is

the binding of

repressor at OL

I

and

Oo I . Bind-

ing at the

first sites is rapidly succeeded

by coop-

erative

binding

of further repressor

dimers at

O12

and O*2.

This shuts off the synthesis

of Cro

and starts

up

the synthesis of repressor

via

Po*.

i

ir:i,ifii

i:;.:r,r The critical

stage

in deciding

between

lysogeny

and

lysis

is when del'ayed

early

genes

are

being

expressed.

If cII causes

sufficient

synthesis

of

repressor,

l"ysogeny

wjttieiutt because

repressor

occupies

the

operators.

Otherwise

Cro occupies

the

operators,

resutting

in

a lytic

cycl.e.

The

initial event

in entering

the

lytic cycle

is

the

binding

of Cro

at

OR3.

This stops

the

lyso-

genic-maintenance

circuit

from starting

up

at

P*r. Cro

must

then

bind

to Ool

or Oo2,

and

to

O.l or Or2,

to

turn

down

early

gene expres-

sion.

By halting

production

of cII

and CIII,

this

action

leads to the

cessation

of

repressor

synthe-

sis

via P*u. The shutoff

of

repressor

establish-

ment occurs

when

the

unstable

cII

and cIII

proteins

decay.

The

critical

influence

over

the

switch

between

lysogeny

and

lysis

is cII.

If cII

is active,

synthesis of

repressor

via the

establishment

pro-

moter is effective,

and

as a

result,

repressor

gains

occupancy

of the

operators.

If

cII

is not active

1.4.21. What

Determines

the

Balance

Between

Lysogeny

and

the

Lytic

cycLe?

373

repressor

establishment

fails,

and

Cro binds

to

the operators.

The

level

of cII

protein

under

any

particu-

lar

set of circumstances

determines

the

outcome

of an infection.

Mutations

that

increase

the sta-

bility

of cII increase

the frequency

of lysogen-

ization.

Such mutations

occur

in c1I itself

or in

other

genes.

The

cause of cIIs

instability

is its sus-

ceptibility

to

degradation

by host

proteases.

Its

level

in the

cell is influenced

by cIII as

well as

by host functions.

The

effect

of the lambda protein

cIII is

sec-

ondary: it

helps to

protect

cII against

degrada-

tion. The presence

of

cIII does

not

guarantee

the

survival

of cII; however,

in the

absence of

cIII, cII is

virtually

always

inactivated.

Host gene products

act on

this

pathway.

Mutations

in the host genes

hflA

and hflB

in

cre a

s e ly s o

geny

-hfl

s tand s f

or high

ft

e

qu

en cy

/ysogenization.

The

mutations

stabilize cII

because

they inactivate

host

protease(s)

that

degrade it.

The

influence

of the

host

cell on the level

of

cII

provides

a route

for the

bacterium

to inter-

fere with

the

decision-taking process.

For

exam-

ple,

host

proteases

that degrade

cII are activated

by

growth

on rich

medium.

Thus

lambda

tends

to lyse

cells

that are

growing

well,

but is more

Iikely

to

enter lysogeny

on

cells that

are starv-

ing

(and

which lack

components

necessary

for

efficienr

lytic

growth

1.

Sum mary

Phages

have

a lytic life

cycle,

in

which infec-

tion

of a host

bacterium

is

followed

by

produc-

tion

of a large

number

of

phage particles,

Iysis

of

the cell,

and release

of the viruses.

Some

phages

also

can

exist in lysogenic

form,

in

which

the

phage

genome

is integrated

into

the

bacte-

rial

chromosome

and is inherited

in

this inert.

latent

form

like

any

other

bacterial

gene.

In

general,

lytic

infection

falls into

three

phases.

In

the first

phase

a small

number

of

phage

genes

are transcribed

by the

host RNA

polymerase.

One or

more

of these

genes

is

a

regulator

that

controls

expression

of the

group

of

genes

expressed

in

the second phase.

The

pattern

is repeated

in the

second

phase,

when

one

or more genes

is

a regulator

needed for

expression

of the

genes

of the

third

phase.

Genes

of

the first

two

phases

code for

enzymes

needed

to reproduce

phage

DNA; genes

of the final

phase

code

for

structural

components

of the

phage

particle.

It

is common

for the

very early

genes

to

be turned

off

during

the later

phases.

CHAPTER

14 Phage

Strategies

In

phage

lambda,

the

genes

are organized

into

groups

whose expression

is

controlled

by

individual

regulatory

events. The

immediate

early

gene

N codes for

an antiterminator

that

allows transcription

of the leftward

and right-

ward

groups

of delayed

early

genes

from

the

early

promoters

PR

and Pr. The

delayed

early

gene

Q

has

a similar antitermination

function

that

allows transcription

of all

late

genes

from

the

promoter

P*,.

The lytic

cycle is

repressed,

and the lysogenic

state maintained,

by

expres-

sion of the cI

gene,

whose

product

is

a repres-

sor

protein

that acts

at the operators

O*

and O,

to

prevent

use

o{ the

promoters

P* and P,

respectively.

A lysogenic phage

genome

expresses

only the

cI

gene

from

its

promoter,

P*no.

Transcription

from this

promoter

involves

positive

autogenous

regulation,

in

which

repres-

sor

bound at

O* activates

RNA

polymerase

at

p

.

RM.

Each

operator

consists of

three binding

sites

for repressor.

Each

site is

palindromic,

consist-

ing

of symmetrical

half-sites.

Repressor

func-

tions

as a dimer.

Each half

binding

site

is

contacted

by a repressor

monomer.

The

N-terminal

domain of repressor

contains

a helix-

turn-helix

motif that

contacts

DNA. Helix-3

is

the recognition

helix

and responsible

for mak-

ing

specific contacts

with

base

pairs

in the

oper-

ator. Helix-2 is

involved

in

positioning

helix-3;

it is also involved

in

contacting

RNA

polymerase

at P*r.

The

C-terminal

domain is

required

for

dimerization.

Induction

is caused

by

cleavage

between

the

N-

and

C-terminal

domains,

which

prevents

the DNA-binding

regions

from

func-

tioning in

dimeric form,

thereby

reducing

their

affinity for

DNA

and making

it impossible

to

maintain lysogeny.

Repressor-operator

binding

is cooperative,

so that

once

one dimer

has

bound

to the first

site, a

second dimer

binds

more

read-

ily to

the adjacent

site.

The helix-turn-helix

motif

is

used

by other

DNA-binding proteins,

including

lambda

Cro.

Lambda

Cro binds

to the

same

operators

but

has

a different

affinity

for

the individual

oper-

ator sites,

which

are determined

by

the

sequence

of helix-3.

Cro

binds individually

ro

operator

sites,

starting

with

O*3, in

a noncooperative

manner.

It is

needed

for

progression

through

the

lytic

cycle. Its

binding

to O*3

first

prevents

synthesis

of repressor

from

P*r,

and

then

its

binding

Io O^2

and

O*I

prevents

continued

expression

of early

genes,

an

effect

also

seen in

its

binding

to O.l

and

Or2.

Establishment

of repressor

synthesis

requires

use of

the

promoter

P*",

which

is

acti-

374

vated

by the

product

of

the c11

gene.

The

prod-

uct of

c111is required to stabilize the cll

prod-

uct against degradation.

By

turning off

cI1 and

c111 expression,

Cro acts to

prevent

lysogeny.

By turning off all transcription except

that of

its own

gene,

repressor acts to

prevent

the

lytic cycle.

The choice between

lysis and

lysogeny depends

on whether repressor or Cro

gains

occupancy of the operators

in a

partic-

ular

infection. The stability of cII

protein

in

the

infected cell

is

a

primarv

determinant of

the outcome.

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Two Types

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the

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octamer.

J Mol.

Biol.3l4,

1127-1136.

Dodd, I. B.,

Perkins,

A. J.,

Tsemitsidis,

D., and

Egan,

J.

B.

(200I).

Octamerization

of

lambda

CI repressor

is needed

lor effective

repression

of P(RM)

and

efficient

switching

from

lysogeny.

Genes

Dev.

| 5,

)Ol3-3022'

References

375

The

Repticon

CHAPTER

OUTLINE

1

l

Introduction

3E7.,

Repticons

Can Be

Linear

or Circutar

r

A replicated

region

appears

as an

eye within nonreplicated

DNA.

r

A replication

fork

is initjated

at the

origin

and then moves

sequentiatly

atong

DNA.

.

Replication

is

unidjrectional

when

a singte reptication

fork

is

created

at an origin.

.

Reptication

is

bidirectjonal

when

an origin

creates

two

repti-

cation forks

that move

in

opposite

directjons.

Origins

Can Be

Mapped

by Autoradiography

and Etectrophoresis

.

Reptication

fork

movement

can

be detected

by

autoradiogra-

phy

using radioactive

putses.

.

Replication

forks

create Y-shaped

structures

that

change

the

electrophoretic

migration

of DNA fragments.

Does

Methylation

at

the

Origin Regulate

Initiation?

o

onC contains

r'

carr

rteven

;iA;

repeats

that

are

methylated

on

adenine

on

both

strands.

r

Replication generates

hemimethylated

DNA, which

cannot

initiate

reotication.

Replication

0rigins Can Be

Isolated in

Yeast

.

Origins

in S.

cerevisiae are

short A-T-rich

sequences

that

have

an essentia[

11-bp

sequence.

e

The

ORC is

a comptex

of six

proteins

that

binds to

an ARS.

Licensing

Factor

Controts

Eukaryotic

Rereptication

r

Licensing factor

is necessary

for

initiation

of reptication

at

each origin.

r

It is

present

in

the nucteus

prior

to reptication.

but is

inac-

tivated or

destroyed

by

replication.

o

Initiation

of another

reptication

cycle

becomes

possibte

onty after

licensing factor

reenters

the nucteus

after

mitosis.

Licensing

Factor

Consists

of MCM Proteins

.

The

ORC is

a

protein

complex

that is associated

with

yeast

origins

throughout

the cetl

cycle.

e

Cdc6

protein

is

an unstabte

protein

that is

synthesized

on[y

in G1.

e

Cdc6

binds

to ORC and

a[tows MCM

proteins

to

bind.

o

When reptication

is initiated.

Cdc6 and MCM

proteins

are

disptaced. The

degradation

of Cdc6

prevents

reinitiation.

o

Some MCM

proteins

are in

the nucteus

throughout

the cycte,

but others

may

enter onty

after mitosis.

D Loops

Maintain

Mitochondria[

Origins

o

Mitochondria

use

different

origin sequences

to initiate

reptication

of each DNA

strand.

o

Reptication

ofthe

H strand is

initiated

in

a D [oop.

r

Replication

of the L

strand is initjated

when its

origin

is

exposed

by the movement

of the first reptication

fork.

Summary

.

There is

a 13-minute

detav before

the

remethvtated.

fflf

,eneats

a'e

0rigins May

Be

Sequestered

after

Reptication

.

SeqA

binds

to hemimethylated

DNA

and is

required

for

detaying

rerep[ication.

.

SeqA may

interact

with DnaA.

r

As

the

origins

are

hemimethytated

they bind

to the

cetl

membrane

and

may

be

unavaitable

to methytases.

o

The

nature

of the

connection

between

the

origin and

the

membrane

is

sti[[

unctear.

Each

Eukaryotic

Chromosome

Contains

Many

Repticons

.

Eukaryotic

replicons

are 40

to 100 kb

in

tength.

e

A chromosome

js

divided

into

many repticons.

o

IndividuaI

repticons

are

activated

at

characteristic

times

during

5

phase.

o

RegionaI

activation

patterns

suggest

that repticons

near

one

another

are activated

at

the same

time.

376

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