Calculated strand breaks from 125I in coiled DNA

TIM GOORLEY1, MICHEL TERRISSOL2, & HOOSHANG NIKJOO3

1Department of Nuclear Engineering, Massachusetts Institute of Technology, USA, 2Laplace, Universite Paul Sabatier,

Toulouse, France, and 3Radiation Biophysics Group, Medical Radiation Physics, Karolinska Institute, Stockholm, Sweden

(Received 2 February 2008; revised 9 September 2008; accepted 15 September 2008)

AbstractPurpose: DNA single strand breaks (SSB) and double-strand breaks (DSB) induced by Auger electrons from incorporated125I decay were calculated using a B-DNA model to assess contributions from direct and OH damage and effects of higher-order structure. Three decay sites, linker DNA, nucleosome, and two adjacent nucleosomes, were assessed and compared toexperimental data.Method: A Monte Carlo track structure code for electron was used to track electrons, OH and H radicals through linear anda higher-order model of B-DNA. Direct and indirect DNA hits were scored and used to determine SSB and DSB.Results: The three different 125I decay locations produced different number of DSBs and fraction of radical damage. Theaverage number of DSB per 125I decay was 0.83, 0.86 and 1.33, respectively, for the three sites. OH radicalattack contributed to or exclusively caused 70%, 57%, and 50%, of the DSBs located in the entire model. When only10 base pairs on either side of the incorporation site were considered, radical damage contributions were 40%, 25% and67%, respectively. Locations distant from the site of incorporation, however, consistently yielded 70–80% of the DSB fromradical attack.Conclusions: Coiling of DNA can greatly change both the absolute number of DSB per incorporated 125I decay and therelative contributions of radical damage to the local site of decay and, to a lesser extent, the average over all DNA. Higherorder structure only slightly affects the number and quality of DNA damage to distant locations, which is mostly from radicalattack.

Keywords: Auger electron, Monte Carlo, track structure, 125I, DNA damage, direct and indirect damage

Introduction

Experimental research in radiation biology, particu-

larly DNA damage, has used 125I extensively. With

its short range and high-LET emissions, the 125I

Auger cascade electrons have been used to probe the

radiosensitivity of specific sub-cellular targets. Early

experiments were focused on targeting the nucleus

and DNA, but now specific genes can be targeted,

and 125I anti-gene radiotherapy investigations for

breast cancer (Nakamoto and Saga 2000), and

thyroid carcinoma (Haberkorn and Henze 2001)

are underway. Even though 125I and other Auger

cascade emitting radioisotopes are being investigated

for advanced therapies, several fundamental ques-

tions remain concerning their effects on mammalian

DNA. The absolute number of SSB and DSB in

mammalian DNA per 125I decay, and the contribu-

tion of radical attack to these breaks, are of concern

in this paper.

A study by Walicka and colleagues measured

CHV79 cell survival (Walicka et al. 1998a) and the

number of double-strand breaks (Walicka et al.

1998b), and deduced contributions of radical and

direct damage to mammalian DNA. Their conclu-

sion that on average, more than one DSB resulted

from each 125I decay, is in contrast to earlier work

with plasmid or linear DNA indicating 0.8–1.0 DSB

per decay. They hypothesized additional damage is

from coiling of DNA in nucleosomes, whereby

regions of DNA *80 base pairs distant are physically

located near the decay site, or from tertiary structure

coiling, involving hundreds or thousands of inter-

mediate base pairs. They also assert that damage to

Correspondence: Dr Hooshang Nikjoo, Radiation Biophysics Group, Medical Radiation Physics, Karolinska Institute, SE17176 Stockholm. Tel:þ46 8 5177 5190.

E-mail: hooshang.nikjoo@ki.se

Int. J. Radiat. Biol., Vol. 84, No. 12, December 2008, pp. 1050–1056

ISSN 0955-3002 print/ISSN 1362-3095 online � 2008 Informa Healthcare USA, Inc.

DOI: 10.1080/09553000802478109

Int J

Rad

iat B

iol D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y W

ake

Fore

st U

nive

rsity

Hea

lth S

cien

ces

on 0

9/24

/13

For

pers

onal

use

onl

y.

these nearby locations is mostly from radical attack.

This increase in DNA damage from nearby DNA

may be offset, however, by the reaction of the histone

support proteins with free radicals, thereby

protecting the DNA against radical attack (Sak

et al. 2000).

Computer simulated radiation transport of the 125I

Auger electron spectra and associated radical diffu-

sion, coupled with atomistic representation of DNA,

is complementary to these experiments, and is used

to investigate these difficult to measure processes.

Earlier simulation efforts for 125I have focused on

linear fragments of DNA (Nikjoo et al. 1996, 1997),

circular plasmid DNA (Pomplun and Terrissol

1994), single nucleosomes (Terrissol 1994), triplex

DNA (Nikjoo et al. 2000, 2006), or quadruplex

DNA (Laughton et al. 2004). Their results agree well

with plasmid DNA experiments. While researchers

have investigated the effects of higher-order structure

on DNA damage from external X-ray (Friedland

et al. 1998, Fulford et al. 2001), gamma, alpha

(Newman et al. 2000) and heavy charged particles

(Holley and Chatterjee 1996), the effects of 125I have

not been investigated until now. These other efforts,

which use solenoid and/or zigzag chromatin struc-

tures, have been used to predict chromosome

aberrations, small fragment production and fragment

size distributions (Holley and Chatterjee 1996). This

paper presents the calculated DNA breaks from 125I

decays in coiled DNA. Both the absolute number of

strand breaks, and the relative contribution of

radicals were calculated.

Materials and methods

DNA model

This paper presents computer simulations of 125I

Auger electron transport, subsequent radical pro-

duction and diffusion, and resulting single and

double strand breaks to coiled DNA. The linear

model of B-DNA including the first hydration shell

was described by Umrania et al. (1995) and used in

the Study by Watanabe and Nikjoo (2002). The

coiled model of a nucleosome and the chromatin

segment were created based on published data and

models of nucleosome by Friedland et al. (1998),

Felsenfeld (1996), van Holde and Zlatanova (1995),

Terrissol and Pomplun (1994), Widom (1989) and

Finch and Klug (1976). Full details of structure

simulation will be reported in a separate commu-

nication. An important aspect of the simulation of

the small or large macromolecular structures is that

the structure should be tested using Molecular

Dynamic techniques. To our knowledge no such

test has yet been reported to large simulated

structures such as nucleosome and chromatin.

To elucidate the effect of DNA coiling, three decay

sites were chosen for the incorporated 125I, which

replaced a methyl group in the base tyrosine. Site A

is a region of linker DNA, with no other DNA in

range of the emitted Auger electrons, and represents

the maximum potential for radical attack. Site B is in

a nucleosome, with an adjacent loop of DNA and a

histone region core, shown in Figure 1. Site C is in

between two adjacent nucleosomes, with both having

histone cores, and represents a minimum of radical

attack. All the sites are identified in the same 40 nm

long solenoid DNA model, shown in Figure 2. The

size of the model exceeds the range of most Auger

electrons and most of the free radicals they create.

Strictly speaking K and L shell electrons and

Figure 1. Atomistic model of nucleosome. The histone core region

shown, as well as a region of linker DNA.

Figure 2. Two orthogonal size view sections of the chromatin

model. The small black dots are where the 125I decays are located.

Site A is a region of linker DNA, site B is in a nucleosome, but is

relatively distant from other nucleosomes. Site C is where two

nucleosomes are adjacent. The 125I atom replaced a methyl group

in tyrosine.

DNA damage by 125I 1051

Int J

Rad

iat B

iol D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y W

ake

Fore

st U

nive

rsity

Hea

lth S

cien

ces

on 0

9/24

/13

For

pers

onal

use

onl

y.

conversion electrons have ranges which could exceed

40 nm.

Electron track simulation and radical transport

For each of these sites, sampled 125I decay electron

spectra were used to specify the number and energies

of the electrons. These electrons were subsequently

transported through liquid water with a Monte Carlo

track structure program. The tracks from the emitted

electrons were randomly superimposed over the

atomistic model and direct hits were scored. Energy

deposition events in the volume of sugar-phosphate

backbone greater than 17.5 eV were scored as single

strand breaks (Charlton and Humm 1988, Nikjoo

et al. 1996, Pomplun et al. 1996). OH and H

radicals, and aqueous electrons, were created and

then transported using random-walk diffusion in

time steps of 1610712s. Radicals were terminated

when they reacted with each other, diffuse 4 nm

away from the model, or after 961079 seconds

following 125I decay. Only reactions of OH radicals

with the sugar-phosphate moiety were considered to

have the probability of causing strand breakage. In

brief, probability of an OH radical causing a strand

break was set at 0.13 (Milligan et al. 1993). Full

detail of the model of damage including the

energetics of DNA damage and probability of OH

radicals causing strand breaks have been published

elsewhere (Nikjoo et al. 1997, 1999, 2001, Nikjoo

and Uehara 2004).

DSB scoring

Strand breaks within 10 base pairs and on opposite

DNA strands were scored as a double strand break.

When one or both of the SSB in a DSB resulted

exclusively from a radical attack, the DSB was scored

as a ‘scavengable’ DSB. The SSB of the same DSB

which resulted from both direct and indirect action

were categorized but not included in the scavengable

contribution.

Results

Double-strand breaks per 125I decay

The average number of single and double-strand

breaks, per 125I decay is shown in Table I. For both

the linker site, site A, and the single nucleosome site,

site B, there were almost equal probabilities that

either one or no DSB occurred. Both also had about

a 15% chance of two DSB, which increased the

average number of DSB per decay to 0.85 for both

cases. Site C, where the 125I was incorporated at a

location where two nucleosomes were adjacent, had

significantly fewer instances of decays with no DSB,

and significantly higher number of average number

of DSBs, 1.33. Three or four DSBs sometimes

resulted from a single decay of 125I for this case with

much higher frequencies than the case A or B. While

the number of 125I decays used in each simulation

varied, the average number of SSB and DSB per

decay is well converged for each case.

Contribution of radical and direct damage

These three decay sites were also evaluated for

contribution of radical damage to the incorporated

and adjacent strands of DNA. The results, shown in

Table II, dramatically varied for each site and also

varied when individual regions of the DNA were

considered. When all DSBs were considered for each

site, the ‘scavengable’ contribution was 70%, 57% and

50%, respectively, for the three cases. When only the

closest 15 base pairs to the incorporated 125I were

considered, the scavengable contribution was 59%,

43% and 28%. For cases B and C, scavengable

contributions to DNA regions adjacent to the incor-

porated strand were 71% and 52%. For all decay sites,

distant DNA DSBs were 80–85% scavengable.

Discussion

This analysis of 125I decays in a coiled DNA model

had several interesting results. Site A, the linker

DNA site, should be comparable to previous linear

DNA simulations. The total number of DSB

remained the same as previous calculations. There

was a large decrease in the number of DSB at the

local site, within 10 base pairs, however, which was

offset by a large number of radical induced DSB at

other locations in the model. For site B, the total

number of induced DSB also agreed with Terrissol’s

nucleosome model calculations of 0.8 DSBs per 125I

decay (Terrissol 1994). Again, these calculations

show significantly fewer DSB at the local site, but an

increased number of radical induced DSB were

Table I. Average number of DSBs per 125I decay.

Per 125I Decay NO DSBs 1 DSB 2 DSBs 3 DSBs 4 DSBs or more Avg # DSBs Avg # SSBs # of decays

Site A 0.42 0.38 0.15 0.03 0.01 0.83 6.5 1000

Site B 0.37 0.45 0.13 0.04 0.00 0.86 5.8 5000

Site C 0.25 0.37 0.22 0.12 0.04 1.33 9.4 1000

1052 T. Goorley et al.

Int J

Rad

iat B

iol D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y W

ake

Fore

st U

nive

rsity

Hea

lth S

cien

ces

on 0

9/24

/13

For

pers

onal

use

onl

y.

located further away. Site C, which had a total

number of DSB of 1.3, also had a large fraction of

DSB located not in the immediate vicinity of the

decay site and the immediate associated region on

adjacent DNA strands. This effect, which appeared

for all three decay sites, is probably due to the

interaction of radicals with nearby DNA, which has

not been modeled in previous calculations. A

question that could be asked is whether the yield of

DSB for the unscavengable effect should be the same

for all three sites. This is a reasonable question but

the geometry of the three sites as discussed above is

sufficiently different to account for the differences

seen in the calculations.

While the number of DSB per 125I decay, 1.3 for

site C, agrees with Walicka et al. (1998a, 2000)

experimental evidence of more than 1 DSB per

decay, it conflicts with their deduced fraction of

radical induced DSB of 80% or more. The calcu-

lated value of 50% for site C indicates much greater

amounts of direct damage. Assuming the 125I decays

in uniform distributions over the three sites this

would raise the radical damage contribution to as

much as 70%, but it would lower the average number

of DSB per 125I decay. This provides a closer

agreement with Walicka et al. (1998b, 2000) experi-

mental results, but still representing less than a

quarter of total DNA double strand breaks. Such

averaging would also lower the average number of

DSB per decay to 0.61+ 0.13 (20% variance with a

95% confidence), approaching less of an agreement

with the more than 1 DSB per decay determined

experimentally.

To understand the reasons for the differences

between the experimental data and the calculated

values we need to seek the explanation in model

parameters and model of damage on the one hand,

and the need to understand the way experimental

data can be interpreted. The model of damage used

in the present calculations has been bench marked

and is similar to the one used in previous work. To

what extent the coiled model of DNA and the

cellular conditions determine the outcome has to be

investigated by alternative methods.

The difference in calculated DSB yields resulting

from the addition of secondary and tertiary structure

in DNA is significantly smaller than those observed

for other radiations. Warters and Lyons (1992) have

shown the DSB yield from X-ray radiation of

CHO cell deprotenized DNA was 8.3 and 4.5 times

larger than the yield from DNA nucleosomes and

chromatin fibres, respectively. Other researchers

have found an additional 3- to 5-fold increase in

the DSB yield for deprotenized DNA over DNA

in chromatin fibre form (Elia and Bradley 1992,

Oleinick et al. 1992).

The model of DNA damage assumes a DSB is

formed when two SSB on opposite strands are

separated by no more than 10 base-pairs (Charlton

et al. 1989, Nikjoo et al. 2001, 1999). Changing the

separation of two SSB, for the formation of a DSB,

to 15, 20 or 25 base pairs does not make appreciable

change to the fraction of radical damage or the

absolute number of double strand breaks occurring

in the different regions. This would cause damage

reported in the ‘other’ column of Table II to be

reported in the ‘Incorporated Strand’ or ‘Adjacent

Strand’ columns. Most of the direct and radical

damage to adjacent DNA strands occurs within

10–15 base pairs.

To estimate the statistical uncertainties in the

calculations, we investigated the effects of various

parameters within the code on the induction of SSB

and DSB yields. Each of these parameters has

experimental uncertainty associated with them,

which propagates to uncertainty in the calculated

results. Another source of uncertainty in the calcula-

tions is the result of the random numbers used in the

Table II. Scavengable contributions to DSBs for three sites with incorporated 125I.

Site A Incorp. Strand Other Total

DSBs/decay 0.46 0.37 0.83

Unscavengable 41% 16% 30%

Scavengable 59% 84% 70%

Site B Incorp. Strand Adjacent Strand Other Total

DSBs/decay 0.53 0.10 0.23 0.86

Unscavengable 57% 29% 16% 43%

Scavengable 43% 71% 84% 57%

Site C Incorp. Strand Adjacent Strands Other Total

DSBs/decay 0.45 0.59 0.29 1.33

Unscavengable 72% 48% 21% 50%

Scavengable 28% 52% 79% 50%

DNA damage by 125I 1053

Int J

Rad

iat B

iol D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y W

ake

Fore

st U

nive

rsity

Hea

lth S

cien

ces

on 0

9/24

/13

For

pers

onal

use

onl

y.

simulations. Random numbers are used to determine

the number and energy of the electron spectra, the

direction they are emitted, the location and quantity

of energy they deposit, the formation of radicals, the

diffusion of the radicals, and the determination of

damage the radicals create in DNA. In order to

understand whether the resulting calculations were

statistically well converged, 5000 decays of 125I were

sampled and the average number of SSB and DSB

were incrementally averaged in groups of 500 decays

to determine the influence of running additional

histories. The plots of the single and double strand

breaks as a function of these progressive averages are

shown in Figures 3 and 4, respectively. This

simulation used an OH activation probability of

0.13, and a 125I decay located in a nucleosome.

These statistical convergence graphs illustrate that

the average number of DSB and SSBs are within 5%

of their ultimate values after 500 decays, and within

3% after 1000 decays.

Conclusions

The results show that increasing the amount of DNA

near a decay site due to coiling may not necessarily

increase the total number of DSB, as in case B, but

can significantly increase the total number of DSB in

certain situations, such as case C. For case B, the

increased direct damage to DNA from nearby coils

of DNA is apparently balanced by the decreased

radical attack, which is caused by the removal of

radicals from the histone core. For case C, the decay

site is virtually surrounded by DNA, and the direct

mechanism has a much greater role. The result from

Figure 3. Average number of SSBs as a function of 125I decays sampled. The % difference from the converged value, the combined average

over the 5000 sampled decays, is also plotted.

Figure 4. Average number of DSBs as a function of number of sampled 125I decays. The % difference from the converged value, the

combined average over the 5000 sampled decays, is also plotted.

1054 T. Goorley et al.

Int J

Rad

iat B

iol D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y W

ake

Fore

st U

nive

rsity

Hea

lth S

cien

ces

on 0

9/24

/13

For

pers

onal

use

onl

y.

this work for the contribution of OH radicals to

induction of DSB per decay is lower than that

deduced by Walicka et al. (1998, 2000) from their

experiment. Although the modelling parameters are

well benchmarked against DNA damage data for

plasmid DNA, we still need to search the differences

in modelling of cellular environment and to what

extent these differ between plasmid and cells.

Acknowledgements

This research was partially supported by DOE grant

to the Harvard/MIT BNCT Program #DE-FG02-

97ER62193 and the Los Alamos National Lab

subcontract H1962-0019-2G.

Declaration of interest: The authors report no

conflicts of interest. The authors alone are respon-

sible for the content and writing of the paper.

References

Charlton DE, Humm JL. 1988. A method of calculating initial

DNA strand breakage following the decay of incorporated

125I. International Journal of Radiation Biology Related

Studies in Physics Chemistry Medicine 53:353–365.

Charlton DE, Nikjoo H, Humm JL. 1989. Calculation of initial

yields of single- and double-strand breaks in cell nuclei from

electrons, protons and alpha particles. International Journal of

Radiation Biology 56:1–19.

Elia MC, Bradley MO. 1992. Influence of chromatin structure on

the induction of DNA double strand breaks by ionizing

radiation. Cancer Research 52:1580–1586.

Felsenfeld G. 1996. Chromatin unfolds. Cell 86:13–19.

Finch JT, Klug A. 1976. Solenoidal model for super structure in

chromatin. Proceedings National Academy Sciences USA 73:

1897–1901.

Friedland W, Jacob P, Paretzke HG, Stork T. 1998. Monte Carlo

simulation of production of short DNA fragments by low-

linear energy transfer radiation using higher-order DNA

models. Radiation Research 150:170–182.

Fulford J, Nikjoo H, Goodhead DT, O’Neill P. 2001. Yields of

SB and DSB induced in DNA by AlK ultrasoft X-rays and

alpha-particles: Comparison of experimental and simulated

yields. International Journal of Radiation Biology 77:

1053–1066.

Haberkorn, U, Henze M. 2001. Transfer of the human NaI

symporter gene enhances iodide uptake in hepatoma cells.

Journal of Nuclear Medicine 42:317–325.

Holley R, Chatterjee A. 1996. Clusters of DNA damage induced

by ionizing radiation: Formation of short DNA fragments. 1.

Theoretical modeling. Radiation Research 45:188–199.

Laughton CA, Grindon C, Girard P, Nikjoo H. 2004. The

mysteries of telomere structure and recognition: Could radio-

probing help? International Journal of Radiation Biology 80:

805–811.

Milligan JR, Aguilera JA, Ward JF. 1993. Variation of single-

strand break yield with scavenger concentration for plasmid

DNA irradiated in aqueous solution. Radiation Research 133:

158–162.

Nakamoto Y, Saga T. 2000. Establishment and characterization of

a breast cancer cell line expressing Naþ/I- symporters for

radioiodide concentrator gene therapy. Journal of Nuclear

Medicine 41:1898–1904.

Newman HC, Prise KM, Michael BD. 2000. The role of higher-

order chromatin structure in the yield and distribution of DNA

double-strand breaks in cells irradiated with X-rays or alpha-

particles. International Journal of Radiation Biology 76:

1085–1093.

Nikjoo H, Girard P, Charlton DE, Hofer KG, Laughton CA.

2006. Auger electrons – a nanoprobe for structural, molecular

and cellular processes. Radiation Protection Dosimetry 122:

72–79.

Nikjoo H, Laughton CA, Terrissol M, Panyutin IG,

Goodhead DT. 2000. A method for radioprobing DNA

structures using Auger electrons. International Journal of

Radiation and Biology 76:1607–1615.

Nikjoo H, Martin RF, Charlton DE, Terrissol M, Kandaiya S,

Lobachevsky P. 1996. Modeling of Auger-induced DNA

damage by incorporated I-125. Acta Oncologica 35:849–856.

Nikjoo H, O’Neill P, Goodhead DT, Terrissol M. 1997.

Computational modelling of low energy electron induced

DNA damage by early physical and chemical events. Interna-

tional Journal of Radiation Biology 71:467–483.

Nikjoo H, O’Neill P, Terrissol M, Goodhead DT. 1999.

Quantitative modelling of DNA damage using Monte Carlo

track structure method. Radiation and Environmental Biophy-

sics 38:31–38.

Nikjoo H, O’Neill P, Wilson WE, Goodhead DT. 2001.

Computational approach for determining the spectrum of

DNA damage by ionising radiation. Radiation Research 156:

577–583.

Nikjoo H, Uehara S. 2004. Track structure studies of biological

systems. In: Mozuumder A, Hatano Y, editors. Charged

particle and photon interactions with matter: Chemical,

physiochemical, and biological consequences with applica-

tions. New York: Marcel Dekker. pp 491–531.

Oleinick NL, Balasubramaniam Xue L, Chiu S. 1992. Nuclear

structure and the microdistribution of radiation damage in

DNA. International Journal of Radiation Biology 66:523–529.

Pomplun E, Terrissol M. 1994. Low-energy electrons inside active

DNA models: A tool to elucidate the radiation action

mechanisms. Radiation and Environmental Biophysics 33:

279–292.

Pomplun E, Terrissol M, Demonchey M. 1996. Modelling of

initial events and chemical behaviour of species induced in

DNA units by Auger electrons from 125I, 123I and Carbon.

Acta Oncologica 35:857–862.

Sak A, Stuschke M, Wurm R, Budach V. 2000. Protection of

DNA from radiation-induced double strand breaks: influence

of replication and nuclear proteins. International Journal of

Radiation Protection 76:749–756.

Terrissol M. 1994. Modeling of radiation-damage by I-125 on a

nucleosome. International Journal Radiation Biology 66:

447–451.

Terrissol M, Pomplun E. 1994. A nucleosome model for the

simulation of DNA strand break experiments. Basic Life

Sciences 63:243–250.

van Holde K, Zlatanova J. 1995. Chromatin higher order

structures: Chasing a mirage? Journal of Biological Chemistry

270:8373–8376.

Umrania Y, Nikjoo H, Goodfellow JM. 1995. A knowledge-based

model of DNA hydration. International Journal Radiation

Biology 67:145–152.

Walicka MA, Adelstein SJ, Kassis AI. 1998a. Indirect mechanisms

contribute to biological effects produced by decay of

DNA-incorporated iodine-125 in mammalian cells in vitro:

Double-strand breaks. Radiation Research 149:134–141.

Walicka MA, Adelstein SJ, Kassis AI. 1998b. Indirect mechanisms

contribute to biological effects produced by decay of

DNA-incorporated iodine-125 in mammalian cells in vitro:

Clonogenic survival. Radiation Research 149:142–146.

DNA damage by 125I 1055

Int J

Rad

iat B

iol D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y W

ake

Fore

st U

nive

rsity

Hea

lth S

cien

ces

on 0

9/24

/13

For

pers

onal

use

onl

y.

Walicka MA, Ding Y, Adelstein SJ, Kassis AI. 2000. Toxicity of

DNA-incorporated iodine-125: Quantifying the direct and

indirect effects. Radiation Research 154:326–330.

Watanabe R, Nikjoo H. 2002. Modelling the effect of incorporated

halogenated pyrimidine on radiation-induced DNA strand

breaks. International Journal of Radiation Biology 78:953–966.

Warters RL, Lyons BW. 1992. Variation in radiation-induced

formation of DNA double-strand breaks as a function of

chromatin structure. Radiation Research 130:309–318.

Widom J. 1989. Toward a unified model of chromatin folding.

Annual Review Biophysics Biophysical Chemistry 18:

365–395.

1056 T. Goorley et al.

Int J

Rad

iat B

iol D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y W

ake

Fore

st U

nive

rsity

Hea

lth S

cien

ces

on 0

9/24

/13

For

pers

onal

use

onl

y.