I I

tr D oSe Yolr^wr e co..'!t(q'vr* tr

rt+.-,-( e-lrr\^ Ca. lruo. Q^, -.fi-i/
So V4" (.4 'r \' ,D ,'\8e.n <*n/' V2.(f,s'\'- 4o V

fen-\".rI l, s-^
-.s-f\\\
< % <=4 t.
,, Vs.( 2S
,fa.r cn- (.{ro-G1
r\ r'*y.-( ros.\'dlGgeriph'I doX.

Eu!_]=: Sefu,Ld-l$- , ^r -( So\i,l

D,.".o.{ sa V*o {.4o'\' Rr*Jrlo! ,f V
fe-"rre.d /,. VAo (es.V
. iooq -.-<.to (e,{,licc I -ca.
E.. a.rV4o -(4"- gc\' , G"<so'\'
6so s Qa.

Fe-ocC [e'J,S*Ss29.
Grd. So..lt B.rrel , \-* ft? . Vj5(35'l'
Lir+ : or..qqr. < S. 9'
lunt /..,r
0ra,.i r,., $a(\v.re . S -,lc G7. S!.eri uul#<1
u\R' 2.ec- (ed*o{Sgx;sl (l+S
V
ze<- ilodau <llLT
JA
t- \\L

Pc..\.s/sl Dr^o*^( \\- 24 c^y $ rca t

ora\ a{i{ D*.^. { t\
\ <!..lft D-.*_ ( R,-\5 G.-,
L."\ []) *^*". { tj 6 Vzo
-<3o
\
L iv<v- D,^o".( tt1. vb(so\vL

--1--

tr J
-
tr tr

E
 6t oi
- i't n'#*- ,S "ib en \wrqc,.its^ .
S\

1
(o

+l- €-

I
(
C)tr ,-o
"r

slEr. v7 .\,-

r
 ?' sl -rE"
'EE.
'_!o-$ aI f q 11 7

-
s',bJ +

_] _]]__
\7
-+--s:15 <-
+-
bt sl

E*: k
(,-. J.xlz

\e;
-a--=
D\s$ll,tFr!5, ]irs- s,
<--
, ;r'
-...---.--\---\J

c\&o
9..=----

/ S-)

bs.r. ^-.
riK
RI Y.atb0 il \

w lG-.2-\16 + 9es$ lo yhll..t.

A. \4

/n
 tr\ 6-

oa

eh.o-.,,-tl ,s- -\

l.nl r...' -.,\(-ve o,l.kt QlL"-a=A----:

rtsk

-l- |

orlst+c/.

@
L-
 '\tq
) A
J<-

T'xtr -La > /;y u.[bb /\(

-1,l_

) -rgtul*q0F.,o
+.d-tt"-"rDr, =-$ ra
\)\\sD
T7ffi sv-@--
_.},vr

EN
"X-\F.,W-
 -.-\..-,+

i1 I

Ao c*y io \5 Fc*c{ il,li't .

{B.rs- loGS i-, 4 kaclbos .

o S\b

.SL

C ('\

€>

ace<\<<+<I
L: Ssc<i [(lr I 6gk
tr
Struciure Name Dose Notes Blndder Volume (%) 15% <80 Gy 15
Baichral olexus Max Dose None .66 Gy 'l
Bladder Volume (%) 25% <75 Gy 15
Br.chi.lpl.xur Volume (%) 5% .60 Gy 'l
Bladder Volume (%) 35% <70 Gy 15
Braiostam Mar Dose None .gcy 2 Blidder Volume (%) 5096 <65 Gy 15
Breinstcm Volume (%) .60 Gy 2 (1% of PTv)
1%
Femoral heads Max Dose None .50 Gy 14
Cochl.a Volum€ (%) 5% <55 Gy 3 Dv.on <45 Gy
Femoral heads Volume (%) 25% 14
Ears (inner,middlcl Mean Dose None <50 Gy 4
Femo,al heads Volume (%) 409. <40 Gy '14
Ey.3 Max Dose None <50 Gy 3
Penile bulb Mean Dose None <52.5 Gy 15
Ey.3
Glonic Lrynr
Mean Dose
Mean Oos€
None
None
:!gil
Gy
<45
4
4 Rectum Volurne (%) 15% <75 Gy 15

Lan3 Mar Dose None <25 Gy 5 16 t) Rectum Volume (%) 25ga <70 Gy
<65 Gy
15

Mandible Max Dose None <70 Gy 2 Rectum Volume (%) 35% 15

M.ndible Volume (cc) <1cc 75 Gy 2 Rectum Volume (%) 50% <60 Gy 15
Optic narves Max Dose None .gcy 2
Opic narves Volurne (96) 1% <60 Gy 2 (196 o, PTv) f@@[ Ma. Dose None <45Gy 16
Or.lc.vity Mean Dose Non€ <40 Gy 3 (excluding PTV)
Plrotid 0land lone) Mean Dose None <26 Gy 6 (f spamg one)
Prrotid glind lonr Volume (%) 50% <30 Gy 6 (if sparing one)
P.rolid glahd (both Volume (cc) <2{kc 20 Gy 6 (if sparing both)
'
Lnipordl lobas Max Dose None .60 Gy 2 ,.rt o{ra{ i o. r)es,..Jt2 O7+

|!fi![[!![volume(%) 'l96 <65 Gy 2 (1% ot Pw)

lff, Dose t',tax None <70 Gy 2
T- ioinr
Tongue
Volume (cc)
Mat Dose
<1cc
None
75 Gy
<55 Gy
2
2
&r.ut
<65 Gy
Tongue Volume 2 (1% of PTv)
ge.rri; Y)t^eqr I ,'S-5 q,
((,6) 1%

Esophagus Mean Dose None <35 Gy 7 (45 Gy if necessary)

Gy necessary)
Esophagu5
Esophigus
Volume (%)
Volume (%)
15%
33%
<54 Gy
<45 Gy
7 (65
7 (50 Gy if necessa.y) L,{Dcy' I < 15
Hearl Volume (%) 33% <60 Gy a
Heirt Volume (%) 67% <45 Gy I lpSr lT, 1io. (( rs-ta)
llein Volume (%) 100% <40 Gy I
ll@@lEil I (lung 4.@
Cr1r.o t-a,
Mean Dose None <20 Gy minus GTV)

@@[@Iilvotume(%) 37% <20 Gy I (lung minus GTV) / S.\'

VtS
Phirvngeal constrictor Mean DosE None .54 Gy 10 *l
Volume (*) 't0
C"&,^ R or1. D-$,.,. < i
Pharyngeal constrictor 51% <50 Gy
Phiryngeal conslrictor

M
Volume (%)

Mar Dose
60%

None
<52 Gy

<60 Gy
10

'tl
7
@il Volume (%) 33% .45 Gy 11

il Volume (%) 33% <50 Gy 12

il Volume (%) 67% <30 Gy 't2

il
LiY€r
Volume (%)
Volume (%)
10096
50%
<23 Gy
<35 Gy
12
13
Volume (%) 100% <30 Gy 13
Max Dose None .50 Gy 14
Volume (cc) <100cc 40 Gy 14
Volume (cc) <180cc 35 Gy 14
Volume (cc) <65cc ,15 Gy 14
Max Oose None .54 Gy 11

Volume (%) 2% <50 Gy 11

Stolnach Volume (%) 25% <45 Gy 11

 $.. *
=, oo &RAA35EC3r33 t3FE533gt:: 34393
969:969A;;963; :6P;69 Y 6;9:6 9:3669696:A 9aa.a
Egs;cEEs
ElrsSrrf r$tls$rg{{t+tr s$rEsrri{*sf tEtsglltEt{ tcl$f
-l{-,r-H-8ll-8-3
IEtEETITStE!II ie,I -E-EE"3"F"g
;:3r IrIrsrEtrtE ,qrBrE
!A !
s
r:rltiii
F iiiirliii;ilii ililE!!r 99t9 t9tttslt9r! {l!i
tr Itgtgslg 9
d)
U)
c
o
.F
o
o -"]
E

Lr : :l
I
|f) J*1, JJ, EB!! HJJJJJ]JJ, E

sBnE533gg:! 38ee3
669.9Y6 9a:6a.6.6636,6. T,}NgYNYY}'NY Hda6666:>64 9a:a:
o
+, lilel9e s$rssitg{*r:cts rtr*$rs{*cr$ lgt$$ti!E!$ rrr$I

F rtslri:
.I
E. rtt9ttl iiriiiiiigtlirF tEriislEa:t:
riii;ii;;i!i
TETsETs,ITE
r9tttr9tlct
!iX Ei
l9i!9
.I
E co
a
C

J .9
o
(g
IL
(f) ,l*l,lJ' 9
ttHut+t lJll*lJJl,ll'
E
(E &E8a365C3SC3 3ree9
L iiiggggg:ugsFE
9a9 a9a.'994
..r.in{io::ci-
$sfgg
bJo !ffESlr$ r$tlsllgl{lett rtrgNrs**rt* Eft$gi$l$l$ tsi*f
o
P at rEisEltE "s"tt"E"E"?
rErtErt{E;st !EtiEEEIEEt
-8"uE
ArI ! r
iiiil
ilii!iii rgrgrgrillriss !iiilI!gcii! -t t9tg9:9t9r9
oa
.I C
3t
o
o
l
o
U)
!
II o
o
(E
?1

:
s
c

o LL I :3 B
I
l6 IJJI,IJ, [l! 0)

zo

iiE rt
E .E .E I
E
t!
TCFE t P !!E !!
: Iilli ::;---;;see
c
- o
= .9
c
a6
rEE?f
466 A 666 66 r d 66 6 d.r6
$tf $s;ii9lE?;gf ?I$$
5 6.rd &
3il93S9RRrBS asaBRgBg:;:83?

'.=
o
!*l**lllltlelrll*{lrlf !: !r;srEl*l*E lrueEsEt€iEt*r 6i$$l(+lsrgu
iiia"FtteFtt'
taaaaalelEa -iiii?i.88R"ti I
o
(E
gEsEEEEiEEEigg ErEEttE:EtEi
ittti!rlliii
Lr
tgiEEii!!riEiEiiiEsiiE!E lrii!rrEl,,-t- !
o
o
(0
c
.9
c
lt
E
:l:
EIE I'
a
0)
F FIF l3
C
o l,l,lf,llJ
l9
H];
ala
,lillJ I l5 HJ: JJ, ;
 6nerJi< .o^o.\,r\c.\

A6l on e f,o,at
nP ,."$6(&- a\rcr b dd-- /t4
t
ayy\o \^<$ " + ra d \.J'\'.,y\ r.rbr h Oa/Vt t ?J .

\"/^
{laL.
s -/)

$ risY t',1. Ut
o
f -t
e*"rr.fA; Chapter 43
Clinical Radiobiology
5e.*el- ,\tn and Physics
4r.;;r l,lF
sa^J.o.f:'"tt, Serah Choi,YooYu, Eleonor A. Blokely, ond John Murnone
ter cl

RADIOBIOTOGY PEARIS
rd ."\( The \.{our Ry'o! Ratliohiolngy (rationale for fractionation o[
r:rdiatlif,i
' Wair - referc to DNA repair in response to sublethal or
polcntiallv lethal radiation damage. Fractionation of radi-
ation allows uoroal tissues time to repaic
I Rgassonnlcnt - .efers to the redistribution of cells into a Q{ Aerliskl[",['].'"
more radiosensitive phase of the cell cycle due to cell cycle
checkpoints after a liaction of radiation.
. Repopulation - refers to tumor cell proliferation during
the coursc of radiation therapy; this can be problematic
lvith prolonged radiation trcatment durations.
. Reorygenation - refers to thc oxygenation of hlpoxic cells
after a fiaction of radiation. Tumors consist of a mixlure
of oxygcnated and hypoxic cells. The orygenated cells are
morc radiosensitive, and therefore oxygenation of hlpoxic
cells during liactionated therapy increases the sensitivity
of tumors to ionizing radiation.
A Filih R has been added to account lbr in vivo dilfer-
in tissue sensitivity
differences in cell metabo-
maturiry of cells in vivo that
when combined explain the differences in the sensitivities
of different tissues.
xilt

O Springcr krlcrnational Publishing AG, pan of Springcr Naturc 2018 893

Eric K Hanscn arxl M. Roach Ill (e<Ii.), lJarrdbook d Etidcnce-Based
Radiation A rcolosr, https://doi.org/1 0. 1007,97 8-3-3 L9 426424 -43

(Puanttc
nsft^q,-! l'g'' .00/".)
Quant;*lire trr"lYsir "t
in +ha e\l^;q h

@
ct) 6, rv ,YrA(f(9 -

c( ( '. ,licrt '

ftr.. \slcr ne/ a"rP*l .

ITt/
ftp.*Jlr\a .

o(J^^ g+aLct (S(r'ld'l-- rrcL^*-\

@t cat o5ok Gr7 L --1

r6iF6ncc 4"J1" S€ns rl i.re

x Q-'. o.tut^J . d*-e'

{ Q-.. ?cne(A^d.

S ca fra/{ cr3
Q\sfn" - *"1c"-J.[. -
lrxla- er tb-lz r:
-- Phd., e'lcrlr"c- -K+
C."*6*-'.' .-fl..h
-
(, Q...\r @roJ.^ef.lon
in R-r

Dos€ e7r^i r. e [,'o\r$<a-( <f;1""1 -2 s''<varl-

"l "',b,

r.\ we\hr"5 lac\orJ I

Phvt".. t 6l ec{ro n ' A qc(o$t{) I

cn*sf "
,l..tcql-fcn s-'l^?
Qfs\on s 2_
A\ho Qort,lLs : Lc"
 tlL $i.<e-\. ' sQce'Atrj e\e<ILos
.;f phcto n br.rA r'
-l Qo.^
)(. \
Uz ind+"S !.<< ro.t.c.dS {r-cn \ro ^

89,1 HANDBooK oF EvTDENcE,BASED RADtATtoN oNcoLoGy

DNA DAMAGEAND IONIZING

RADIATION
DNAlrs lhe clitical target lor radiation-induced cell
t'Iiffilit,.
G(-
r Photons produce their effects through dircct action ll3)
aidi ilirect acrion (-2l3). Direcr acrion r?GGi6i66iiiiii
inteiaEtion-ofE-ser-ond-arielectron(resultingf romabsorp-
tion of an X-ray photon) with DNA. Indirect action refers
to DNA damage caused by fr-ee radicals produced through
the ionization of H2O by a secondary electron.
r DNA damage to the cell can come in several forms:
rg t Base &mage: repaired via base excision repair, not a
g1f do'"'1e "
major contributor to radiosensitivity, except in the case
of XRCCI deficiency.
@ t Sngie-sd breaks (ssBs): repaired via single-strard
on$ir'\ : .r-I
2-* brcak repai4 not a major contributor to radiosensitivity.

v4? :{ ' Doubte-sUrd breals (DSBs): repaired via homologous

recombination repair (in late S/G2, when a DNA tem-
plate is available), which is accurate; or nonhomolo-
)/ ? gous end-joining, which is error-prone. DSBs are the
most important radiation-induced lesions in terms of
cell killing.
G; ! Chromosomal and chromatid aberrations: rcsult from
unrepaired or misrepaired DSBS. SYmmetric transloca-
tions and small deletions tend to be nonlethal, but are
frequently involved in carcinogenesis Lethal aberra-
tions include acentric fragments, rings, dicentric chro-
mosomes, and anaphasc bridges.
r LE? (linear energy transfer) - refers to the average energy
transferred to tissue per unit length of an ionizing particle
(in keV/pm). Generally, heary particles like alpha particles
or iron ions have high LET, while photons and protons
have lower LET.
t RBE (relative biological effectiveness) = (dose of 250 keV
X-rays or 6oCobalt orr3TCesium gamma rays required for a
given effect)/(dose from a different type of radiation to
yield the same effect). The greatest RBE for cell killing
occurs when LET reaches 100 keV/pm since this is the
diameter of a DNA double helix.

e
 'b.A-zpoJ1)S
-
-' 5
f4lrurfrl Yr&1 r'oe15/rs 3
frqsq t33a/a >J
ra -r1,t{
fi**Br4 -
f?'1\ta\Y"'')]Pul
e\*,

s /.u v,t ';rlrP ll'l9+ l^lb,l yl" \=

u6,r+2u
",P-f
NP
r z+v
L s=sJ r 76b ?

f, uh 2-ilrl

oV Yp -).,?tA\ 9.r,p*d bl Qo,

y | 0/t-
tr lu ,r1ir19r).j
tP+ Un
P\ 1C

7)
o.'o2
Dlp
T F:iT, ru - 03f!

J S.E S,' Jr \
*) tb q)
,)
s7 8\ c'y ,
^y'?
't+1pg&oq i- ol -S :.t--5o861'
\-_-=\-
- t'rf "tn'
I -}€ll"ai",..r
V
r l\\".,0
or4
.r,y?
J^ 5'O

'.^B* oS yu.,rt*:: g
. .oa( aa d

: s1\ql\ asof ct'q )f\N i

 cHAPTER 4l: CLINIcAL RADIOBIOLoGY ANO PHYslcs 895

CELL SURVIVAL CURVES

' A cell suwival cuwe is a graph of the relationship between
radiation dose and the surviving fraction of cells that
retained their reproductive integrity (clonogenic). Dose is
plotted on a linear scale (x-axis) and surviving fraction on
a logarithmic scale (y-axis).
. The multitarget model descibes survival curves in terms
of an initial slope, D,, which results Irom single-event kill-
ing and a final slope, D6, which results from multiple-
event killing where the curve approximates a straight line
at higher doses. Dr and Do are thc reciprocals of the initial
and final slopes and represent the doses of radiation that
induce an average of one lethal event per cell, leaving 377o
of the cells still viable. The extrapolation number (n) and
quasithreshold dose (Dq) are measures of the width of the
shoulder of the cuwe. Dq is the dose below which there is
minimal effect. The multitarget model was largely dis-
carded because it is not consistent with our cturent under-
standing of cell killing by ionizing radiation.
r For a t]?ical mammalian cell, the Do is between I artd
2 Cy and results in >1000 damaged bases, -1000 SSBS,
and 40 DSBs per cell.
r The D1o is the dose requaed to kill 904la of the popula-
tion=2.3xDo
r'lhe linear-<truadratic model (tQM) describes radiation-
induced cell killing as a linear-quadratic function of dose.
At low doses, DSBs are likely to be caused by a single pho-
ton or particle, and aberrations are directly proportional
to dose (linear). At higher doses, DSBs are likely to be
caused by two separate photons or particles, and are pro-
portional to the squarc of the dose (quadratic). The lin-
ear-quadratic model is more consistent \\'ith our current
undcrstanding of ccll killing bv ionizing radiation.
r According to the LQM, S = e{o-0D^'z, where S = surviving
fraction, and a and g represent the linear and quadratic
components o[ cell killing, respectively The initial slope is
xil!
determined by a, while the p causes the cur.ve to bend at
higher doses.
, The unitersal surttfuol nlodel ((tSM) has recently been pro-
posed to account for the fact that the LQM does not
 qlr''tJ. b,,'ala- "I I t"-r 4* l"\.
SP< nr^tra:
$. I

olor< rqk e hor$ < ."ohl5,

8 's- o,.J
fu"Y
1leJore
frro?f
dissqo
ee ' b<kv<Po'

fr". c*i o r,+ io 11

-

C F, - 2- [ s lvteertl atdoS='l Ls-3F F'- '

A.8

\ryee<-f, Al -4,L f ,,lo t v{eekt , tJi:} ' * 6 o- Jo fr *"*).. d.x7l"l'

4.1:f_i
f, ,.rr- r- f > slw.u l>alai, +
t\yf,-F, >Lall <ttdo5 f 4s*"'x
!ro.*i..
t[ra"r*. kolr.l'A f ,,

Ulr-- F, J trD /rs

U Or<rc,ll Jqrq+("'r "(-{ft
ue on ar*l
/
*isse Q.
J RQ{'J'*I'.' '
LJe l'l o

.fqr\ SE ) cF
*{Y Ac-,+" S c
L""{ <. Ss ( C-F
LoFe 36
---J

Sg\i'., C"*-{54 p\ar{

\\70' - r i'rlerr.Urt.An l" .f ac{,< 56-

- u-tc^ ,Jly P"/f.

€",r\ 3b s cF
i-'ah< se CF
 896 HANDBooK oF EVTDENcE-BASED RAorATroN oNcoLoGy

accurately predict radioresponse at higher doses per frac-

tion due to the continuous slope in the predicted curve.
The USM is a combination o[ the LQM and the multitarget
model at higher doses per fraction, with Dr (6 Gy) as the
transition point.
. Most tumors and eerly-responding tissues (e.g., mucosa)
have a high trlfl ratio (- l0), whereas some nrrnors (e.9.,
prostate) and late-respon.ll'g tissues (e.g., spinal cord)

\r v.. $rqdl" nq\ to,\ .

havc a lorv 0y'9 ratio (-3).
When lreatments are tractronated, sublethal damaee
( S L D ) calqq-t€E3.lled be wee n r rea t m e ;Gfi
r is-lo;s
a
the "shc,ulder" oI the survival curve to be repeated, thereby

z lJ.rI B'$ sparing late-responding tissues. This is the basis for

hloerfraction{tion during which treatments are given
{.>{\s
v'
\r\< t"\ st c-i.i
twicc pcir dav ,rr mr)re t,r mitigatc late cllccts.
I The biotofictifzffialent dose IBE]D) refers to the effective
total absorbed dose (in Gy) for a given fractionation $
scheme i[ it were given bv standard liactionation (1.8-
2.0 Gy/day).
r For the IQM:
(
r
BED = nd[ I + d/(q/p)], where n = number of fractions
and d = the dose per fraction. *(P
For the USM:
Below Dr(6Gy): BED = nd[ I + &(dp)l, same as LQM.
Above D1(6Gv): BED = ([ l/q x D,,] x [(D - n) D"J), where
'
D,, is the final slope of the survival curve, and Do is the
quasithreshold dose.

MECHANISMS OF RADIATION-
INDUCED CELL DEATH
(Milotic cell death: cellular death while attempling to
divide due to damaged chromosomes; the most common
cell death mechanism following ratliation in cancer cells:
death can occur in the first or subsequent divisions fol-
tion.
a poptos programmed cell death; occurs in some nor-
(lvmphocltes, embryonic development) and
can occur in some tissues after radiation; dominant cell
 CHAPTER 43: CLINICAL RADIOBIOLOGY AND PHYSICS 897

death mechanism in lyrnphoid cells following radiation;

characterized by cytoplasmic condensation, cell shrink-
age, apoptotic bodies, chromatin condensation, and DNA
Fagrnertation.
'Necrosis: can be either non-programmed cell deaLh by
altrlysis, r-,r programmed t}rough a process called
necloptosis.
. Autophagic cell death: evolutionarily conserved self-diges-
tive process regulated by autophagy-related genes (Atgs).

iF
It involves the sequestration of poftions of the cytoplasm
into double membrane vesicles called autophagosomes,
which fusc with lysosomes, leading to degradation of pro-
teins and organelles.
. Cellular senescence: a programmed cellular stress
response to the accumulation of damage to a cell that
'r i
results in irreversible cell cycle arrest. ;t
THE CEtt CYCLEAND DNA
REPAIR
%
r Thc ccll cycle for mammalian cells can be dividcd into G1 7
(initial growth phase) - S (DNA replication phase) - G,
(additional growth phase) + M (mitotic phase during C^' stt'
which chromosomes are evident). In general, M phase is
the most radiosensitive, and late S/early G2 phase the most
radioresistant portion of the cell cycle.
r Transition through the cell cycle is governed by cyclins
and cyclin-dependent kinases (CDKs). The important cell
cycle checkpoints include:
r 5,, + S is governed by cyclin D1/CDK4/6 and cyclin E/
CDK2.
I S is governed by cyclin UCDK2.
r G, - M is govcrned by cyclin B/CDKI.
'DNA damage activates cell cycle checkpoint pathways,
which inhibit the progression of cells through the cell
cycle, allowing for DNA repair before mitosis. xill
r Retinoblastoma (pRb) is a tumor suppressor protein that
restricts Gr + S. When a cell is ready to divide, the CDK-
cyclin kinase complex phosphorylates pRb, releasing
pRbi inhibition of E2F, a transcription factor that binds
 898 HANDBooK oF EV|DENcE-BASED RADIATToN oNcoLocy

to the promoter region of genes whose protein products

are essential for S phase.
. p21 (ClPlMAFl) protcin is a CDK inhibitor (CKl) that
regulates cl - s; it binds to and ifibits cyclin D-CDK6,
cyclin D-CDK4, and cyclin E-CDK2 complexes. p2l can
also mediatr ccllular scncsccnec.
r pl6hrr"(CDKN2A) is a tumor suppressor protein that
inhibits S phase by binding to CDK4/6, inhibiting cyclin
D-CDK4/6 complex lormation and CDK4/6-mediated
phosphorylation of Rb family members.
r ATM, ATR, and DNA-PKcs are members of the phosphati-
dylinositol 3-kinase-related kinzrse (PIKK) family, are acti-
vated by DNA DSBs, and function as kinases that regulate
'Jst ( t--! DNA repair and cell cvcle proteins.
p53 is a tumor suppressor protein that functions in cell
€ '
cycle regulation, DNA repair, and apoptosis. It is a tran-
oS <./
<:'
scription factor that activates the expression of several
gencs, including p2l (CDKN I A), GADD45, and apoptotic

r} ost S
genes. In unstressed cells, p53 is negatively regulated by
MDM2, an E3 ubiquitin ligase that targets p53 for pro-

td 2 )r', r
tcasomal dcgradation. DNA DSBS activatc ATM (or ATR
if DSBs are at the replication fork), resulting in the phos-
phorylation of p53, thereby preventing its degradation
bv MDM2.
DSBs are repaired by either nonhomologous end-join-
ing (NHEJ), which involves proteins DNA-PKCS, Ku70,
Ku80, Artemis, XRCC4, PNK, XLF, and DNA ligase IV; or
homologous recombination repair (HRR, also known as
HDR, homology directed repair), which involves proteins
MRE!l, Rad50, NBSI, RPA, BRCAI, RAD5I, BRCA2,
RAD52, and RAD54. 53BPl inhibits homologous recom-
bination. NHEJ is inaccurate, but can occur anytime in
thc cell cycle, whilc HRR is accuratc, bul can only occur
in late S/early Gz.
. Most DSBs (80-90'lo) are repaired within l-2 hours, while
the remaining DSBs take many hours to repair. Some
DSBs (multiply damaged sites or in heterochromatin) are
much more difficult to repair than others, and along with
HRR acc()unt for thc DSBs that are slow to bc rcpaired.
r Base damage is repaired by base excision repair, which
involves a glycosylase, AP endonuclease (creating a SSB),
PNKP and then polp, DNA ligase IIl, XRCCI for
 Ts- yr\c\rSei.c lesf

S+ o-r'd** i(k, 73r GT c, r 3\ '\q ..s.d*.t (r{.5

^...J-J..J.'V ( s k ) t,s ei r$,$a^ql i
-TCQ
(,
-
23 t, FR (
S(SK

$i:=\ rirkr -Sr.qf$

31 +d.lt /ols 7
I Chr,r^o.
4* sc,\qs:

11

r- +
f D

{l t
t ,1O
\9
)
v
 Ser'.nq.0 crr"\ ) 4s-5",4 €l
t r^o\nq Qro,t'-' 54- Co A I
-> L t

+re&+...lp<^A
+_._....--

-x.S.,i^- ! Alol @goJ,^-^^,,o..-,

^ur
r-s ffstrlr0l
T
T se> BGGtr.
"'.\ T

+ ,Qi\"
"grGtJ- #llq- +

C\ z->6bser.,
R.Tr2- S>, y'-ti 6 ( s,,+ - 54 Gl)

retedL..,.

+ 5]t" 'tao =) /d' s4 o c^v)

,,3q(^
s4-(6 \Y
56r .<\-e-
-4eu
T -| 2."4 \
+ C6 OG
(4. c
s\
SF \t\-9.

4QS: c -|a
I

-------J+-

il
tr tr
C.\ /-

b E-rs-
o

/A sr- H hJ h- ,^V ,^lcrssa/ef*

Sta $..^t"s)A < wJoo

- Lisfsaelo-t ,p", ".li e,ha,",

no

tt
)(/r) l$Yu (tu,)' J-N/'1q
2> L+t+ <+L
3)--+ertJ:
Lvx- "ld9
9 -- -
s) -eLslrt -g lthn-
d rsr
tlp./"r&n'
{\ P ttry-zr clar<-

tr
I
E
I
tr n

t-

l
+
L $ F]
-