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A B ST R A C T

K

E

N

D R

A A

.

W

O

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E Y

.

h O G G

l

S

e r3 2

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i ga r et te

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ok

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d

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k

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fr

o

m

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)

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i

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t

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l i g

n an t

b

r e a st t

i

s s u e

h

a

d 9

.

7 6

-

f

o

l d h i

g

h

e r

l

e v e

l

s o

f

o x

i d i

z e

d g

u a n

i

n e r e s

i d

u e s,

8

-

h

y

d

r o x

y

-

2

'

d

eox

y g

u a n o s

i

n e

(

8

-

O H d G

)

t

h

a n n o r

m

a

l b

r e a st t

i

s s u e

(M

u s a r r at, et a

l

,

19 9 6

)

.

A

not

h

e r stu

d

y r epo rte

d

s

i

gn

i

f ic a nt

l y h i gh

e r

l

e v e

l

s o

f

8-

O H d G i

(6)

t

h

a n

i

n t

h

e c o ntr o

l

s, t

h

o ug

h

t

h

e stan

d

a r

d d

e v

i

at

i

o n o

f

c o n c e ntr at

i

o n s

w

e r e w

i d

e

(

L

i

, et a

l

,

2 0 0 1

)

.

O f

c o u r s e

, t

h

e e

l

e v ate

d l

e v e

l

s o

f

o x

i d

at

i

v e

d

a

m

age c o u

l d b

e a c a u s e o r a r e s u

l

t

o

f

t

h

e c a n c e r.

To

d

e s c r

i b

e t

h

e

m

e c

h

a n

i

c s o

f

t

h

e

m

uta

g

e n es

i

s, gu an

i

n e

p

r e

f

e r s to

p

a

i

r

w i

t

h

cyto s

i

n e

,

b

ut o x

i d i

z e

d

gu a n

i

n e o

f

te n

m i

s

-pa

i

r s w

i

t

h

a

d

e n

i

n e. T

h

e r e s ult

i

n

g

str a n

d h

a s a n

a

d

e n

i

n e op po s

i

te t

h

e o x

i d i

z e

d

gu an

i

n e. Du r

i

n g t

h

e n e x t r e

p l i

c at

i

o n cyc

l

e, t

h

e

m i

s

-p

a

i

r e

d

a

d

e n

i

n e

w i l

l c a u s e a tr a n s v e r s

i

o n

m

utat

i

o n

i

n t

h

e

d

a u g

h

te r str an

d

,

w h

e n t

h

e a

d

e n

i

n e t

h

e n

pa

i

r s w

i

t

h

a t

h

y

m i

n e

(

B

r u n e r

, et a

l

,

2 0 0 0

)

.

O

x

i d i

z e

d

gu a n

i

n e s s u c

h

a s

8

-

h

y

d

r o xy gu a n

i

n e

(

8

-

O H

-

G

) (

Bo

i

te u x an

d R

a

d i

c e

l l

a,

2 0 0 0

)

an

d 8

-o x o

gu an

i

n e

(

8

-o x -o -

G

) (

N

a s

h

, et a

l

,

1

99

7

)

c a u s e t

h

e s e

G

:

C

to

T

:

A

tr a n s v e r s

i

o n s

d

u r

i

ng

D N A

r ep

l i

c at

i

o n

(

Bo

i

te u x an

d

R a

d i

c e

l l

a,1

9 9 9

)

G

:

C

to T :

A

tr an s v e r s

i

on s ar e t

h

e se c on

d

m

o st c o

m

m

o n t

y p

e o

f

s o

m

at

i

c

m

utat

i

o n

f

o u n

d i

n

h

u

m

a n c a n c e r s

(

B

r u n e r, et a

l

, 2

0 0 0

)

. T

h

us, r epa

i

r o

f

o x

i d

at

i

v e

d

a

m

a

g

e

i

s e s s e nt

i

a

l

to

m

a

i

nta

i

n t

h

e

i

ntegr

i

t y o

f

D

N A

.

M

o st o x

i d

at

i

v e

D N A d

a

m

age

i

s r e

p

a

i

r e

d

v

i

a t

h

e

m

u

l

t

i

-p

r ote

i

n,

b

a s e e x c

i

s

i

on

r epa

i

r

(

B E

R

)

pat

h w

ay a s s

h

o

w

n

i

n

F i

gu r e

3

(

N i l

s e n a n

d

BCr o

k

a n , 2

0 0

1

)

. T

h

e

h

u

m

a n

B

E R

pat

h w

ay u t i l

i

z e s the 8-o x o

gu a n

i

n e g l yc o sy la s e

/

apu r

i

n

i

c

l

ya s e

(

h O G G

l

)

to r e

m

o v e

o x

i d i

z e

d p

u r

i

n e

b

a s e s

i

n

D N A

a n

d

c r e ate a n a

b

a s

i

c s

i

te

(

D h

e r

i

n , et a

l

, 1

9 9 9

)

. T

h

e

h O G G l g

e n e

h

a s a n o n -s

y

no n

y m

o u s s

i

n

g l

e n u c

l

e ot

i d

e po

l

y

m

o r

p h i

s

m

(

SN P

)

at c o

d

o n

32 6

t

h

at c a u s e s a c

h

ange

fr

o

m

a

S

e r

(

T C C

)

to a

C

ys

(

T

G C

)

r e s

i d

u e. T

w

o stu

d i

e s r e

p

o rte

d

r e

d

u c e

d

e n zy

m

at

i

c a ct

i

v

i

t

y f

o r t

h

e

C

ys a

l l

e

l

e

(

K

o

h

n o , et a

l

,

19 9 8

;

D h

e r

i

n, et a

l

,

19 9 9

)

T

h i

s s ug ge sts t

h

at a

h O G G

l

C

ys3 2

6

ge n oty pe

m

ay

l

e a

d

to e x c e ss

i

v e a

m

o u nts o

f

o x

i d i

z e

d

(7)

Expo s u r e to ciga r et te s

m

ok e and polych lo rin ate d b i p he n yls

(

P C Bs

)

c an le ad to

o x

i d

at

i

v e

d

a

m

age o

f

D

N A i

n t

h

e

h

u

m

a n

b

o

d

y. Bot

h

c

h

e

m

i

c a

l

s a

l

s o ha v e

p l

a u s

i b

le

m

e cha n

i

s

m

s fo r

i

n v o

l

v e

m

en t

i

n c a n c e r

d

e v elop

m

e nt. T

h

u s,

i

n

d

iv

i d

u als

w i

t

h

de

f

i c

i

e nt

r epa

i

r

m

e chanis

m

s

m

ay

b

e

m

o r e s u s c e

p

t

i b l

e to c anc e r

i f

e xpo s u r e s

b

u r de n t

h

e

i

r r epa

i

r

c apa c

i

t y.

C i g

a r et te s

m

o

k

e c o nta

i

n s c

h

e

m i

c a

l

s t

h

at y

i

e

l d

R

O S

in viv o an

d l

e a

d

to

f

o r

m

at

i

o n o

f 8

-

O H

-

G

r e s

i d

u e s

, e s

p

e c

i

a

l l

y

i

n

l

u n g t

i

s s u e

(

A

s a

m

i

, et a

l

, 1

9 9 7

)

.

H

o

w

e ver,

b

r e a st c a n c e r stud

i

e s to

d

ate r e

p

o rt a r a n

g

e o

f p

o s

i

t

i

v e to

i

n v e r s e a s s o c

i

at

i

o n s

b

et we e n

c

i

ga r et te s

m

o

k i

ng a n

d b

r e a st c an c e r

(

T e r ry an

d

Ro

h

a n , 2 0

0

2

)

. L

i p

o

p h i l i

c

P C

Bs c a u s e

R

O S

to a c c u

m

ulate

i

n

f

at ty tis s u e s,

i

n c

l

ud

i

n g br e a st t

i

s s u e

(

O

a

k l

ey, et a

l

, 1 9

9

6

)

.

Ho

w

e v e r,

m

o st stu

d i

e s

h

a v e s

h

o

w

n n o o v e r a

l l

a s s o c

i

at

i

o n

w i

t

h b

r e a st c a n c e r r

i

s

k

a n

d

s e r u

m

P

C

B

l

e v e

l

s

(W

o

l f f

, et a

l

, 1

9 9 3

; Kr

i

ege r, et a

l

,

19 9

4 ;

C

a

l l

e, et a

l

,

2 0 0 2

)

.

T

o e v a

l

u ate t

h

e a s s o c

i

at

i

o n o

f h O G G

l

3 2 6 g

enot y

p

e s

w i

t

h

e n v

i

r o n

m

e nta

l

e x po s u r e s to ci ga r et te s

m

oke a n

d

P

C

Bs, a nd

b

r e a st c a n c e r r

i

s

k

,

w

e ge n oty pe

d D N A

s a

m

p le s a n

d

ut

i

l

i

z e

d d

ata

fr

o

m

t

h

e

C

a r o

l i

n a Br e a st

C

a n c e r

S

tu

d

y

(

C

B

C S

)

.

C

B

C S i

s a

p

o

p

u

l

at

i

on

b

a s e

d

c a s e-c o ntr o

l

stu

d

y o

f A fr i

c a n

A

m

e

ri

can a n

d

n on-

A fr i

c a n

A

m

e

ri

c a n

w

o

m

e n

i

n

N

o rt

h C

a r o

l i

n a.

W

e ge n ot y

p

e

d

2 0 2 5 c a s e s a n

d

1 8

1

3 c o ntr o

l

s

fr

o

m

t

h

e

C

B

C S

a n

d

a n a

l

yz e

d

po s s

i b l

e a s s o c

i

at

i

o n s

w i

t

h

e x ta nt

d

ata o n s

m

o

k i

n g a n

d

P

C B

e x

p

o s u r e s.

S

E L E

C T

I

V E R

E

V I

E

W

h O G G

l

T h

e

h

u

m

a n

8

-o x o

g

u a n

i

n e g

l

yc o s

y l

a s e

/

a

p

u

ri

n

i

c

l

ya s e,

(

h O G G l

)

g

ene

h

as

b

e e n

m

ap pe

d

to c

h

r o

m

o s o

m

e

3

, r eg

i

o n

2

5

(

Ra

d i

c e

l l

a, et a

l

, 1

9 9 7

)

o r

2 6

(

Sh i

n

m

u r a, et a

l

,

(8)

fr equ e ntl y

m

is sing fr o

m

the chr o

m

o s o

m

al c o nte nts o

f

tu

m

o r c e

l l

s,

i

n c

lu

d i

ng

b

r e a st c a n c e r

c e

l l

s

(

Br u n e r, et a

l

, 2 0

0 0

)

T he a s s o c

ia

tio n

b

et

w

e e n th

i

s

l

o s s o

f h

ete r o zy

g

o s

it

y

(

L

O H

)

o

f

3 p 2 5-2

6

a n

d

tu

m

o r

i ge n e s

i

s c o ul d

in

d

ic ate t

h

e

i m

po rta n c e o

f

h

O G G

l

in

m

a

i

nta

i

n

in

g t

h

e

D N A

sta

b i l i

t y t

h

at

i

s u

b i

qu

i

to u s

l

y

m is s

in

g

fr

o

m

a n e up

l

o

i d

c a n c e r c e

l ls

.

Du r

i

n g tr a n s

l

atio n ,

h O G G l m

R

N A i

s sp

l i

c e

d

to c r e ate t

w

o

i

s o

f

o r

m

s o

f

t

h

e

pr ote

i

n , a

l

p

h

a

-

h O G G l

a n

d b

eta-

h O G G

l

.

A l

p

h

a

-

h O G G

l

, the

d

o

m

in a

nt

i

s o

f

o r

m

,

i

s

c o n str u cte

d

o

f 34

5 a

m i

n o a c

i d

s a n

d i

s

d

e st

i

n e

d f

o r t

h

e n u cle u s,

w

h

i l

e

b

eta

-

h O G G

I

i

s 4 2 4

a

m in o

a ci ds

in

le ngt

h

a n

d i

s

d

e st

in e

d f

o r the

m i

to c

h

o n

d

r

ia

(

Bo

i

te u x a n

d

Ra

d i

c el la, 1 9

9 9

)

F i g

u r e 4

i l l

u str ate s

h

o

w

the a

l p h

a an

d b

eta

i

s o

f

o r

m

s s

h

a r e t

h

e

f

i r st s

ix

e x o n s,

w h i

c

h

cor r e spo n

d

s to t

h

e

f

i r st

3 16

a

m

i

n o a c

i d

s

(

B

o

i

teu x an

d R

a

d i

c e

l l

a,

19 9 9

)

.

A l p h

a

-

h O G G l

e n

d

s

w i

th e x o n s e v e n

w h i l

e

b

eta-

h O G G

I

in c o r

po r ate s a

d i f f

e r e nt e x o n

d

o

w

n str e a

m

t

h

at

r ep

l

a c e s e x o n s e v e n

(

Bo

i

te u x an

d

Ra

d i

c e

l l

a,

19 9 9

)

.

h

O G G

l r emo v e s o x

i d i

z e

d

gu a n

in e r e s

i d

u e s

fr

o

m

D

N A

. I t spe c

i fi

c a

l l

y r e c ogn

iz e s

a n o x

i d i

z e

d g

u an

in e o

p

p

o s

i

te a cyto s

i

n e o r a t

h

y

m

in e

(

S h i

n

m

u r a, et a

l

,

19 9 7

;

R

a

d ic e

l l

a,

et a

l

. ,

19

9

7

)

. T

h

e

h O G G

l

p

r ote

in

e x

h i b i

ts t

h

e

h

e

l ix

-

h

a

ir

p i

n-

h

e

l i

x

(

H h H

)

str u ctu r e that

i

s

co

m m

o n to

p

r ote

in s o

f

the

b

a s e

-e x c

is

io n

r epa

i

r

f

a

m i l

y

(

N

a s

h

, et a

l

, 1

9 9

7

)

.

I

n t

h

e

H h H

s

i

te, the c ata

l

y t

ic

g

lu

ta

m i

n e 2

4 9

at tr a cts t

h

e e

le

ctr o n s o

f

the

C

-1 p

o s

i

t

i

o n o

f

the

de o xyr

i b

o s e s u

g

a r , a n

d

c a u s e s t

h

e r e

le a s e o

f 8

-o x o-

G

(

F

i

gu r e s

5

a n

d 6

) (

Br u n e r, et a

l

,

2 0 0 0

)

h O G G

l at ta c

h

e s

d i

r e ct

l

y to t

h

e D

N A

str a n

d

c o nta

in

i

n

g

t

h

e 8 -o x -o-

G

, c

le a v e s

the

d

a

m

age

d

r e s

i d

u e

(

Br u n e r, et a

l

.,

2 0 0 0

)

a n

d l

e a v e s a n a

p

u r

i

n

i

c s

i

te v

i

a

b

eta

-e

l i

m

in a

tio n

(

R

a

d i

c e

l l

a, e^a

/

.,

19 9 7

)

.

T

h

e

h O G G

l ge n e

i

s po

l

y

m

o rp

h i

c at s e v e r a

l

s

it

e s.

h O G G l S

e r

3

2

6 C

ys

h

a s

b

e e n

(9)

a nd, the r efo r e, o n l y af fe cts the structur e of al p ha

-h O

G

G l

, the iso for

m

that loc aHze s to

t

h

e n u c

l

e u s.

A

n

i

n

i

t

i

a

l f

u nc t

i

o n a

l

stu

d

y o

f S

e r

3

2

6 C

ys r epo rte

d

t

h

at a n

E

c o

l

i

c o

m

p le

m

e ntatio n a s s ay s

h

o

w

e

d

a s

i

gn

i f

i c an t

d

e c r e a s e

i

n r epa

i

r a ct

i

v

i

t y o

f C

ys

3

2 6

c o

m

pa r e

d

to

S

e r

3

2

6

(

K

o

h

n o

, et a

l

.

, 1

9 9 8

)

.

K

o

h

no

, et a

l

, s e

p

a r ate

l

y a

d d

e

d h O G G l S

e r

3 2 6 a nd

C

ys 3 2 6 to a

m

utan t E c o

l

i str a

i

n that la cke

d

t

h

e

h O G G

l

h

o

m

o

l

ogs

M

ut

M

a n d

M

utY w

h i

c

h

n o r

m

al l y r epa

i

r 8-

O

H-

G

, a n

d m

e a s u r e

d

t

h

e ge n e r at

i

o n o

f

spo nta n e o u s

m

utat

i

o n s

i

n t

h

e E. c o

l i

c o

l

o n

i

e s a s a

i

n

d i

c ato r o

f p

r ote

i

n a ct

i

v

i

t y.

A

n ot

h

er stu

d y

m

e a s u r e

d h O G G

l 3 2 6 r epa

i

r e

f fi

c

i

e n cy

b

y

m

e a s u r

i

ng t

h

e r ate o

f

e x c

i

s

i

o n o

f

8-

O

H -

G

fr

o

m g

a

m m

a-

i

r r a

d i

ate

d

D

N A

, a n

d

s

h

o

w

e

d

a 1.

6

-

f

ol

d l

o

w

e r e x c

i

s

i

o n r ate

f

o r t he v a r

i

a nt

C

ys 3 2

6

;

h

o

w

e v e r , d

i f f

e r e n c e

i

n e x c

i

s

i

o n r ate s o

f

t he t

w

o pr ote

i

n s

w

e r e n ot stat

i

st

i

c a

l

l y

s

i

gn

i f

i c a n t

(

D

h

e r

i

n , et a

/

,1

9 9

9

)

.

M

o st r e c e nt l y

, D r. Ju n

N

a

k

a

m

u r a a n

d D

r.

J

a

m

e s

Sw

e n

b

e r

g

, at t

h

e

U

n

i

v e r s

i

t

y

o

f N

o rt

h C

a r o

l i

n a at

C h

a

p

e

l H i l l

,

d

e v e

l

o

p

e

d

an a ss ay t

h

at

m

e a s t i r e s apu r

i

n

i

c s

i

te s a s an

i

n

d i

c at

i

o n o

f p

r ote

i

n

f

u n ct

i

o n . T

h

e

i

r

d

ata

(

u n

pu

b l i

s

h

e

d

)

,

s up po rt a

d

e c r e a s e

d

a ct

i

v

i

t

y

o

f h O G G

l

C

ys 3 2 6 T

h

u s, t

h

r e e

d i f f

e r e nt a s s a

y

s r epo r t

d

e c r e a s e

d

r e

p

a

i

r a ct

i

v

i

t y

f

o r

h O G G

l

C

ys

3

2

6

; yet, n o n e o

f

t

h

e a s s ays

m

e a s u r e

d h

u

m

a n in

vitr o r e

p

a

i

r.

Po

l

yc

h l

o r in ate

d

B ip

h

e ny

l

s

P

o

l y

ch

l

o r

i

n ated

b i

p

h

e ny l

(

P

C

B

)

d

efi n e s a

f

a

m

i l

y of ch lo r

i

n ate

d

o r

g

a nic

c o

m

po u n

d

s.

T h

e

m

o

l

e c u

l

a r s

k

e

l

eto n

i

s c o

m

pr

i

s e

d

o

f

t

w

o

b

enz e n e r

i

n

g

s

(

F i

gu r e

7

)

. T

w

o

to te n c

h l

o r

i

ne ato

m

s c a n re

p l

a ce t

h

e

h y d

r o

g

e n ato

m

s o

f

t

h

e

b i p h

e n

y l

stru ctu r e to c r e ate a

po

l

yc

h l

o

ri

n ate

d b i p h

e ny

l

.

T h

e c

h l

o

ri

n e ato

m

s c a n a r r a n

g

e a r o u n

d

t

h

e c or e

ri

n gs

i

n

2 09

(10)

pr ope rtie s. Fo r e x a

m

p le, s o

m

e c o nge n e r s a ct a s cyto chr o

m

e P 4 5 0

i

n

d

u c e r s, a nd /o r

h

a v e

e str oge n

i

c e

f

fe cts, a n

d /o r

e x h

i b i

t

d i

o x

i

n

-l

i k

e a ct

i

v

it

y

(M

oys

i

c

h

et a

l

, 1

9

9

9

)

. T

h

e r a nge

o

f b i

o

l

og

ic a

l a ct

i

v

it

y

i

s c e rta

in

l

y a s o u r c e o

f h

e a

l

th c o n c e r n s T

h

e

y

a r e c o n s

i d

e r e

d

to

b

e a

h

e a

lt

h h

a z a r

d b

y t

h

e Env

ir o n

m

e nta

l

Pr ote ct

i

o n

A

ge n cy an

d h

a v e

b

e e n

l i

n

k

e

d

to s o

m

e

f

o r

m

s o

f

c a n c e r.

M

etabol is

m

of PCB s c a n le a

d

to fo r

m

atio n of R

O S

a nd o xi

d

ativ e

d

a

m

age.

S

pe c

i fi

c a

l l

y

, cy to c

hr o

m

e

P

4

50 w

i l l m

eta

b

o

l i

z e P

C

Bs

w it

h f

e

w

e r c

h l

o r

in e a

to

m

s

to R

O S

(

O

a

k l

ey, et a

l

,

19 9 6

)

.

Fr o

m

the 1

9

3 0

'

s to the

la

te 1 9 7 0's, P

C

Bs we r e u s e

d i

n

m

an u

f

a ctu r

i

n g. T

h

ey

w

e r e

p

r

i

m

ar

i l y

u s e

d i

n e

l

e ctr

i

c a

l

e

q

u

i p

m

ent

b

e c a u s e o

f

the

i

r

f l

a

m

e

-r e s

i

sta nt n atu r e.

C h l

o r

in

e

ato

m

s rep

la c e

the

f la

m

m

a

b l

e

h

y

d

r oge n ato

m

s o n t

h

e

b i

p

h

eny

l

r

i

n

g

to y

i

e

l d

a n o n¬

f la

m m

a

b l

e s u

b

sta n c e t

h

at

w

a s

fr

e

q

ue nt

l

y u s e

d i

n tr an s

f

or

m

e r s, h y

d

r a u

l i

c

f lu

i d

s,

r efr i ge r ato r

m

oto r s, he at

in

g c o

i

ls, a

i

r c o n

d

i t io n e r s a n

d

t

y

pe

w

r

it

e r s

A

c c o r

d i

n

g

to the

O h io

S

tate

U

n

iv e r s

i

ty Exte n s

io n

w

e

b

s

i

te, P

C B

s

w

e r e u s e

d

to

m

a n u

f

a ctu r e c e r e a

l b

o x e s,

p

la s

t

ic s

, v a r n

i

s

h

e s a n

d

pa

i

nts, to

l i

st o nl y a

f

e

w

c o

m

m

o n pr o

d

u cts

(

h

tt

p

://o

h i

o

l i

n e.o s u .e

d

u

/

c

d

-

f

a ct

/ 0

2

0

1

.

h

t

m l

)

.

I

n 1

9

7

9

,

P C

Bs

w

e r e

b

a nne

d fr

o

m

a

l l

m

a n u

f

a ctu r

in

g

in

the

U

n

i

te

d S

tate s.

H

o

w

e v e r, P

C

Bs

p

e r s

is

t

in

t

h

e e n v

i

r o n

m

e nt. T

h

ey a r e n ot r e a

d i l

y

b

r o

k

e n

d

own

b

y

m

ic r o o rga n

i

s

m

s o r ot he r e n v

ir o n

m

e nta

l

pr o c e s s e s, a n

d

t

h

ey a r e

in c r e a s

in

g

in

the

e n v

ir o n

m

e nt a s

la n

d f

i

l l

s

l

e a c

h

P

C

Bs

i

nto gr o u n

d w

ate r. T

h

e s e

l i

p

i d

-s o

lu

b l

e c

h

e

m i

c a

l

s

a r e a

b

s o r

b

e

d

a n

d p

a s s e

d

u

p

t

hr o u

gh

the

f

o o

d

c

h

a

i

n.

O

n e o

f

t

h

e

b i g g

e st c o n c e r n s o v e r

(11)

Tobac co

Sm

oke

To

b

a c c o s

m

o

k

e c o nta

i

n s n u

m

e r o u s c a r c

i

n oge n s

i

n c

l

u

d i

n g po

l y

cyc

l i

c a r o

m

at

i

c

h y

d

r o c a r

b

o n s

(

P A

H

s

)

, a r o

m

at

i

c a

m

i

n e s, an

d N

-n

i

tr o s a

m i

n e s

(

Te r ry a n

d

Ro

h

a n, 2 0

0

2

)

T he U pop

h i l i

c c a r c

i

n ogen s

i

n t

h

e s

m

o

k

e c a n

b

e tr a n spo rte

d

a c r o s s t

h

e a

l

v e o

l

a r

m

e

m

b

r a n e

into the b

l

o od str e a

m

a n

d

, e v e ntu al

l

y, sto r e

d i

n a

d i

po s e tis s u e s s u c

h

a s

i

n t he

b

r e a st

(

Te r ry a n

d R

o

h

a n, 2

0 0

2

)

. T

h

e s e c a r c

i

n o

g

e n s o

ft

e n

f

o r

m b

u

l k

y a

d d

u cts o n t

h

e D

N A

w

h

i

ch c a n

l

e a

d d i

r e ct

l

y to

m

utat

i

on s.

M

eta

b

o

l i

s

m

o

f

s o

m

e c

h

e

m

i

c a

l

s

i

n to

b

a c c o s

m

o

k

e

f

o r

m R O S

a n

d

r e su

lt

i

n

f

o r

m

at

i

o n o

f

ox

i d i

z e

g

u a n

i

n es.

T h

u s, a

p l

a u s

i b l

e

p

at

h w

a

y

e x

i

sts

f

o r a n a s s o c

i

at

i

o n

b

et

w

e e n c

i g

a r et te s

m

o

k i

ng an

d b

r e a st c an c e r.

H

o

w

e v e r, r e s u

l

ts

l i

n

k i

ng

b

r e a st c a n c e r to c

i g

a r et te s

m

o

k i

n g

h

a v e

b

e e n

in c o n s

i

ste nt

(

Te r ry

&

Ro

h

an , 2 0 0 2

)

.

A

r e c e nt

l i

te r atu r e r e v

i

e

w

c o

m p i

le

d d

ata

fr

o

m

popu lat

i

o n-

b

a s e

d

c a s e-c o ntr o

l

s stu

d i

e s o

f

c

i

ga r et te s

m

ok

i

ng a n

d b

r e a st c a n c e r r

i

s

k

,

l i

ke

t

h

e

C

a r o

l i

n a

B

r e a st

C

a n c e r

S

tu

d

y.

F

o r s

m

o

k i

n

g d

u r at

i

o n o

f

s

m

o

k i

ng

f

o r

m

o r e t

h

a n

2 0

ye a r s, t

h

e c o

m

p

i l

at

i

o n

l i

ste

d

o n e stu

d

y t

h

at r e

p

o rte

d

a pr ote ct

i

v e a s so c

i

atio n

(

O

R

0 7

,

9 5

% C

I

0

.5

-

0

.9

)

, o n e stud y w i t

h

n o a s s o c

i

at

i

o n

(

O R

1.2

,

9

5

%

C

I 0.

8

- 1

.7

)

, a n

d

two

stu

d i

e s

w i

t

h

po s

i

t

i

v e a s s o c

i

at

i

o n s

(

O

R 1.

3

, 9 5

% C

I 1.1

-1.

8

;

O

R 1 6

, 9 5

% C

I 1.1

-2

.3

)

(12)

F I

G

U

R

E

S

F i gu r e 1. De o x y

g

u a n o sin e

O

H N

H

2

N

N

'

N H

-

N

:

0

\

d R

F i

g

u r e

2

.

8

-o x -o-

d

(13)

J

^

B ifu n ctio n al D M A

« oxor.* 1 olv c o sv la s e

3'

-B-lv a s e

J

3'

-tri m min

g b y

^

\

. H A PI o r PolB

J

J

m

U

1

PolB

X R C C 1

i

i

s

m

I

Lialllc x

Poip

X R C C1

F i g

u r e

3

.

Sh

or t

P

atc

h B

a s e

E

x c

i

s

i

on

R

e

p

a

i

r

P

at

h w

a

y

h O G G

l is a

b

i

f

u n ct

i

o n a

l D N A

g

l

yc o sy

l

a s e

i

n v o

l

v e

d

in t

h

e

f

ir st ste

p

.

(

A dapted fr om N i ls e n a nd Kr oka n, 2 0 0 1

)

Mig f i

. _

—A

A

1 I 2 ; 3

.

h

i

i

i

l

r

F i gu r e

4

.

h O G G l E

x ons

O

n e to

E i

g

h

t an

d S

p

l i

c

i

ng

A

r r an

g

e

m

ent

(14)

10

G ln3 1 S G ly 4 2

Phe3 1 9 -•

E

l ♦- C ys2 5 3

Val 2 5 0

As n1 5 1

H IS2 7 0

^

®

j

si

^

4

As nI SO / / G lr\2 4 9

» As n1 4 9

9

n

T yr2 0 3

Arg 1 5 4 Afg 2 0 4

3'

F i g

ur e

5

.

8

-o x o-

G

u an

i

n e

i

n

D N A S

tra n

d

a n

d h O G G l I

nte r act

i

o n

W

i

t

h N

u

m

b

e r e

d

A

m

i

n o

A

c

i d

s

i

n

B l

ue

(

A dapted fr o m Br u n e i,eta l , 2 00 0

)

<

>

;

F

i gur e

6

.

3

-

D

vi

ew o

f

li

O G G l

at ta c

h i

n

g

to

8

-o x o-

G

8

-o x -o-

G

, r e

d

,

i

n t

h

e c e nte r o

f

t

h

e

p

ictu r e is

f l

i

p p

e

d

o ut o

f

t

h

e

h

e

l i

x a n

d

s

i

ts

i

n t

h

e act

i

ve s

i

te o

f h O G G l

,

p

ur

p l

e r

i b b

o n s a n

d

r e

d

a r r ow s

(15)

1 1

^ '

n^ (I O-n)

Po l ych lo rin ated B ip he ny l

(

P C B

)

(16)

M

A T E R I A L S A N D

M

E T

H

O D S

S

tu

d

y Pop u

l

atio n

D eta

i l

s of t

h

e

C

B

C S

stu

d

y popu

l

at

i

o n a n

d

r e s u

l

ts spe c

i f i

c a

l l

y c o n c e r n

i

ng s

m

o

k i

ng

a n

d

P

C

B e x

p

o s u r e

w

e r e

p

r e v

i

o u s

l

y r epo rte

d

( M

i l l i k

a n

, et a

l

, 1

9 9 8

;

M

i l l i k

a n , et a

h

,

2 0 0 0

)

Br

i

e

f l y

, t

h

e

C

B

C S i

s a

p

o

p

u

l

at

i

o n -

b

a se

d

c a s e

-c o ntr o

l

stu

d y

t

h

at e n r o

l l

e

d

a tota

l

o

f

4 3

3

3

w

o

m

e n

fr

o

m

2 4 c o u n t

i

e s

i

n e a ste r n a n

d

c e ntr a

l N

o rt

h C

a r o

l i

n a, age s

2 0

-

7

4

,

w i

t

h

i

n v a s

i

v e a n

d i

n-s

i

tu

b

r e a st ca n c e r an

d m

atc

h i

n

g

c o ntr o

l

s

(

N

e

w

m

a n, et a

l

, 1

9 9 5

)

.

A g

oa

l

o

f

t

h

e

C

B

C S w

a s to o v e r

-s a

m

p le

A fr i

c a n

A

m

e r

i

c an

w

o

m

en a n

d w

o

m

e n u n

d

e r t

h

e age o

f

5 0. Ra c e

w

a s s el

f

r epo rte

d

. T

h

e 2

%

w

h

o r e

p

o rte

d N

at

i

v e

A

m

e r

i

c a n o r

H i

spa n

i

c we r e

c atego r

i

z e

d

a s n o n-

A fr i

c a n

A

m

e r

i

c a n

.

C

a s e s

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References

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