细胞凋亡及周期阻滞基本信号通路

(transposition)

< /p>

指

DNA

链重组使其中一段核苷酸链方向 倒置、或从一处迁移

到另一处。

5.

双链断裂

已如前述，对单倍体细胞一个双链断裂就是致死性事件。

（

2

）

THE CONSEQUENCES OF DNA INJURY

The outcome of DNA damage is diverse and generally adverse

（有害的）

. Acute effects arise from

disturbed DNA metabolism

（新陈代谢）

, triggering

（启动，

控制）

cell-cycle arrest or cell death.

Long

term

effects

result

from

irreversible

mutations

（转变，突变，变异）

contributing

to

oncogenesis

（）

.

●

Many Lesions

（损伤）

Block

（阻碍）

Transcription

（转录）

—

an outcome directly related

to

gene

length.

This

has

elicited

（引出）

the

development

of

a

dedicated

repair

system,

transcription-coupled repair (TCR), which displaces or removes the stalled RNA polymerase and

assures high priority repair. TRANSCRIPTIONAL STRESS, arising from persistent blockage of RNA

synthesis,

constitutes

an

efficient

trigger

for

p53-dependent

apoptosis,

which

may

be

a

significant anti-cancer mechanism.

●

Lesions

Also

Interfere

With

DNA

Replication

（复 制）

—

Recently,

a

growing

class

of

DNA

polymerases

（聚合酶）

, numbered ζ to κ, was disc

overed which seems devoted specifically to

overcoming

damage-induced

REPLICATIONAL

STRESS.

These

special

polymerases

take

over

temporarily from the blocked replicative DNA polymerase-

δ/ε, and possibly from pol α . …But this

solution generally comes at the expense of a higher error rate. In fact, this process is responsible

for

most

of

damage-induced

point

mutations

and

is

thus

particularly

relevant

for oncogenesis.

Nevertheless, translesion polymerases still protect the genome.

●

Double-strand

DNA

breaks

(DSBs)

induced

by

X-rays,

chemicals

or

during

replication

of

single-strand breaks (SSBs) and presumably during repair of interstrand crosslinks are particularly

relevant for the recombination machinery.

Eg

：

Cells

with

specialized

DNA

recombination

activities,

such

as

B-

and

T-cells,

may

be

very

sensitive to DSBs when they are rearranging their immunoglobin or T-cell- receptor genes. This

explains

the

frequent

involvement

of

these

genetic

loci

in

oncogenic

translocations

in

leukaemia(

白血病

) and lymphomas

（

淋巴瘤）

and the preferential induction of these cancers by

ionizing irradiation.

Eg

：

DSBs also pose problems during mitosis

（有丝分裂）

, as intact

（未受损的）

chromosomes

are a prerequisite

（先决条件）

for proper chromosome segregation

（分离）

during cell division.

Thus, these lesions

（损伤）

frequently induce various sorts of chromosomal aberrations

（染色

体病 ）

, including

aneuploidy

）

, deletions

（

缺失）

(loss of heterozygosity, LOH) and chromosomal

translocations

（迁 移，置换）

—

events which are all intimately associated with carcinogenesis

（癌变）

.

●

The

cell-cycle

machinery

somehow

senses

genome

injury

and

arrests

（阻滞）

at

specific

checkpoints

in

G1,

S,

G2

and

M

to

allow

repair

of

lesions

before

they

are

converted

into

permanent

mutations.

Lesion

detection

may

occur

by

blocked

transcription,

replication

or

specialized

sensors.

When

damage

is

too

significant,

a

cell

may

opt

for

the

ultimate

mode

of

rescue by initiating

（开始）

apoptosis

（凋亡）

at the expense of a whole cell

什么分子可作为

DNA

双链断裂

/

损伤的标志？用什么方法测定？

（

1

）

Senescence(

衰老

),

can

be

triggered

when

te lomeres

（端粒）

—

the

ends

of

linear

chromosomes

—

cannot

fulfil

（执行）

their

normal

protective

functions.

Here

we

show

that

senescent

human

fibroblasts

（纤维原细胞）

display

molecular

markers

characteristic

of

cells

bearing DNA double- strand breaks.

These markers include nuclear foci of phosphorylated histone

H2AX

and their co- localization with

DNA repair and DNA damage checkpoint factors such as

53BP1, MDC1 and NBS1

. We also show