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500 Charged Particle and Photon Interactions with Matter
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503
19
PhysicochemicalMechanisms
of
Radiation-Induced
DNA
Damage
David Becker
Oakland University
Rochester,
Michigan
Amitava Adhikary
Oakland University
Rochester,
Michigan
Michael D. Sevilla
Oakland University
Rochester,
Michigan
Contents
19.1 Introduction: Overview of Radiation Interaction with Biomolecules...................................504
19.1.1 Radiation
Deposition ................................................................................................505
19.1.2
Ion-Radical
Formation..............................................................................................505
19.1.2.1
Oxidative
Pathway, Hole Transfer, and Reaction.......................................506
19.1.2.2
Reductive
Pathway, One-Electron Adduct Formation...............................506
19.2
Pathways in Direct-Type Effects...........................................................................................509
19.2.1 DNA
Holes (Electron Loss) Trapped Radicals after Low LET Irradiation
atLow
Temperatures ................................................................................................509
19.2.1.1
Radicals
Found after Irradiation at 77
K ...................................................509
19.2.1.2 The
Role of Hole Transfer........................................................................... 510
19.2.1.3
Multiple Oxidations Centered on a Single dG
•+
......................................... 511
19.2.1.4 Inuence
of the Protonation State of the One-Electron
OxidizedGuanine
in DNA on the Mechanism of the Formation
of8-oxo-G
Cation Radical......................................................................... 511
19.2.2
DNA
Electron-Gain Trapped Radicals after Low LET Irradiation at 77
K............. 512
19.2.2.1 Base Radicals Found after Irradiation at 77K........................................... 512
19.2.2.2 Low Energy Electron (LEE): Dissociative Electron
Attachment(DEA) ..........................................................................512
19.2.2.3 Theoretical
Treatment of LEE-Induced Strand Breaks............................. 513
19.2.3
Strand
Breaks from Direct-Type Effects .................................................................. 514
19.2.3.1
Direct-Type Effect Strand Breaks and Free Radical Yields ...................... 515
19.3 Charge
Transfer Processes in DNA: Summary of the Mechanisms .................................... 516
19.4
Linear
Energy Transfer Effects ............................................................................................ 518
19.4.1
Introduction .............................................................................................................. 518
19.4.2 Free
Radical Yields at 77
K ...................................................................................... 518
504 Charged Particle and Photon Interactions with Matter
19.1 introduCtion: overview oF radiation
interaCtion
with b
iomoleCules
In this chapter, recent ndings are presented that elaborate the free radical and molecular mecha-
nisms of radiation damage to DNA. This chapter gives an overview of this area emphasizing recent
ndings. A series of previous reviews and books should be consulted for a more comprehensive
understanding of the eld (Bernhard, 1981; Becker and Sevilla, 1993, 1998, 2008; Ward, 2000;
Bernhard and Close, 2004; Sevilla and Becker, 2004; von Sonntag, 2006; Becker et al., 2007, 2010;
Close, 2008; Kumar and Sevilla, 2008a). The ndings covered in this chapter come from a variety
of laboratories and lead to an improved understanding of the processes that lead to radiation-induced
damage to DNA, beginning with initial energy deposition events, the subsequent formation of radical
intermediates, and, ultimately, the formation of diamagnetic products and strand breaks. Although
the physics of energy deposition of ionizing radiation and the eventual biologically signicant end-
points have received substantial attention, it is the intervening radiation-induced free radical mecha-
nisms and subsequent molecular product formation that have been less investigated and are the focus
of this chapter. Direct-type effects of radiation on DNA are emphasized as these events account for
about half the amount of the cellular DNA damage for low linear energy transfer (LET) radiation
and become the dominant effect, as the LET of the radiation increases (Bernhard and Close, 2004;
Sevilla and Becker, 2004; von Sonntag, 2006; Becker et al., 2007, 2010; Becker and Sevilla, 2008;
Close, 2008). Direct-type effects include both the direct effect, which is the direct ionization of DNA,
and the quasi-direct effects, which include those ionizations of the rst hydration shell and its near
environment that transfer holes and non solvated electrons to DNA (Becker and Sevilla, 1993, 1998,
2008; Becker et al., 2007, 2010; Close, 2008). ESR studies suggest that the waters of hydration that
contribute to the quasi-direct effect extend out to 9 or 10 waters per nucleotide (La Vere et al., 1996;
Becker and Sevilla, 1998; Ward, 2000). The indirect effect of radiation chiey results from hydroxyl
radicals produced from radiation damage to water molecules beyond 10 waters per nucleotide but
still within a few nanometers of the DNA strand (O’Neill, 2001; von Sonntag, 2006). Electrons and a
few hydrogen atoms formed on water ionization also contribute to the indirect effect (O’Neill, 2001;
von Sonntag, 2006). The radiation-produced hydroxyl radicals are the chief damaging agent from
the indirect effect (O’Neill, 2001; von Sonntag, 2006). However, each of the water radical species is
19.4.3 Strand Breaks and Damage Clusters from Heavy-Ion Direct Effects...................... 521
19.4.4 Damage by Soft and Ultrasoft X-Rays ..................................................................... 522
19.5 Excited
States of Ion-Radicals as DNA Damage Precursors ............................................... 522
19.5.1
Sugar–Phosphate
Damage via Excited States of DNA Base Ion-Radicals ..............522
19.5.2
Formation of One-Electron Oxidized Purines ......................................................... 523
19.5.3 Formation of Sugar Radicals .................................................................................... 525
19.5.3.1 Monomeric Model Compounds ................................................................. 525
19.5.3.2 DNA-
and RNA-Oligomers and DNA....................................................... 527
19.5.4
The
Protonation State of One-Electron Oxidized 2′-Deoxyguanosine .................... 530
19.5.5
The Protonation State of One-Electron Oxidized Guanine
indsDNA-Oligomers: The Role of Base Pairing...................................................... 531
19.5.6 Factors Affecting the Sugar Radical Formation from Excitation
of CationRadicals................................................................................................ 533
19.5.6.1 Site
of Phosphate Substitution.................................................................... 533
19.5.6.2
Protonation State of One-Electron Oxidized Purine and pH .................... 533
19.5.6.3 Photoexcitation: Effect of Temperature ..................................................... 534
19.5.6.4 Wavelength of Photoexcitation................................................................... 534
19.6 Conclusion ............................................................................................................................ 534
Acknowledgments.......................................................................................................................... 535
References...................................................................................................................................... 535
PhysicochemicalMechanisms of Radiation-Induced DNA Damage 505
largely scavenged by the high concentration of histone and other proteins in the DNA environment
(Becker and Sevilla, 1993; Jones et al., 1993; O’Neill, 2001; von Sonntag, 2006).
19.1.1 radiation depoSition
As high-energy radiation (photon, electron, or heavy-ion particle) passes through matter, energy
loss occurs in the form of ionizations and excitations (Bethe equation) (Magee and Chatterjee, 1987;
Chatterjee and Holley, 1993; Kraft and Kramer, 1993; Goodhead et al., 1994; Schuhmacher and
Dangendorf, 2002; Friedland et al., 2003; Jakob et al., 2003; Nikjoo and Uehara, 2004; Swiderek,
2006), in approximate proportion to electron density at the specic site. For low LET radiations,
about 90% of the energy loss is in the form of ionizations, with 10% in the form of excitations. Low
LET electromagnetic radiations such as γ-radiation and x-rays ionize and excite molecules largely
via the Compton effect, with the photoelectric effect contributing at lower energies (Magee and
Chatterjee, 1987; Chatterjee and Holley, 1993; Kraft and Kramer, 1993; Goodhead et al., 1994;
Schuhmacher and Dangendorf, 2002; Friedland et al., 2003; Jakob et al., 2003; Nikjoo and Uehara,
2004; Swiderek, 2006). Low LET radiations are relatively sparsely ionizing, creating local clusters
of ions called spurs, blobs, and short tracks. Secondary-electron track ends create short tracks of
higher LET damage (Magee and Chatterjee, 1987; Chatterjee and Holley, 1993). High LET charged
particles, such as α-particles, protons, and ion-beams, produce a dense trail of ionizations that have
a core of ionized and excited molecules and a surrounding penumbra of damage by secondary
electrons (Magee and Chatterjee, 1987; Chatterjee and Holley, 1993; Bernhard and Close, 2004;
von Sonntag, 2006; Becker et al., 2007, 2010; Becker and Sevilla, 2008; Close, 2008). In the pen-
umbra, damage similar to that produced by γ-rays is seen, especially as the distance from the core
increases (Magee and Chatterjee, 1987; Chatterjee and Holley, 1993; Bernhard and Close, 2004;
von Sonntag, 2006; Becker et al., 2007, 2010; Becker and Sevilla, 2008; Close, 2008). The distinct
spatial characteristics of the energy deposition, that is, track structure, from these various radiations
(high LET vs. low LET) have signicant effects on the resulting damage (Magee and Chatterjee,
1987; Chatterjee and Holley, 1993; Kraft and Kramer, 1993; Goodhead et al., 1994; O’Neill, 2001;
Schuhmacher and Dangendorf, 2002; Friedland et al., 2003; Jakob et al., 2003; Nikjoo and Uehara,
2004;
Swiderek, 2006; von Sonntag, 2006) (also see Chapters 13 and 14 for more details).
Although
the initial ionizations by γ-radiation and heavy ions are directly related to the electron
density, the subsequent ionizations by secondary electrons, as they lose energy, eventually come
from only from the outer valence electrons (Becker et al., 2007). This is because the initial ioniza-
tions induce a cascade of secondary electrons that have lower and lower energies, so that eventually
all
ionizations are from the outer valence electrons (Becker et al., 2007).
19.1.2 ion-radical forMation
Ionization creates sites of electron loss (a hole or cation radical) and an ejected electron. Most
ejected electrons, after thermalization, will contain electron-gain sites (radical anion) (Bernhard,
1981; Becker and Sevilla, 1993, 1998, 2008; La Vere et al., 1996; Ward, 2000; Bernhard and Close,
2004; Sevilla and Becker, 2004; von Sonntag, 2006; Becker et al., 2007, 2010; Li and Sevilla, 2007;
Close, 2008; Kumar and Sevilla, 2008a). The radical anions and cations formed account for over
80% of the radical species formed in DNA by low LET radiation (La Vere et al., 1996; von Sonntag,
2006; Becker et al., 2007, 2010; Li and Sevilla, 2007; Becker and Sevilla, 2008; Close, 2008; Kumar
and Sevilla, 2008a). Excitations alone do not lead to a measurable radical formation for low LET
radiation; however, recent evidence shows that excitations of ion-radicals induce biologically sig-
nicant damaging events including strand breaks (Becker et al., 2007, 2010; Becker and Sevilla,
2008; Kumar and Sevilla, 2008a). Low energy electrons (LEE) of less than 20eV have the potential
to directly get added to DNA and undergo dissociative electron attachment (DEA) (Boudaïffa et al.,
2000; Bernhard and Close, 2004; Sevilla and Becker, 2004; Bald et al., 2006, 2008; Simons, 2006;
506 Charged Particle and Photon Interactions with Matter
Swiderek, 2006; von Sonntag, 2006; Becker et al., 2007, 2010; Becker and Sevilla, 2008; Close,
2008; Kumar and Sevilla, 2008a; Sanche, 2008). Although the initial radical formation from DEA
for low LET radiation may be only a few percent of the total production, LEE can target sites such
as the sugar–phosphate backbone and create biologically signicant damage sites (Boudaïffa et
al., 2000; Bernhard and Close, 2004; Bald et al., 2006, 2008; Simons, 2006; Swiderek, 2006; von
Sonntag, 2006; Becker et al., 2007, 2010; Li and Sevilla, 2007; Becker and Sevilla, 2008; Close,
2008;
Kumar and Sevilla, 2008a; Sanche, 2008).
19.1.2.1
oxidative
p
athway,
h
ole
t
ransfer,
and r
eaction
Radiation induction of one-electron oxidations results in a number of major reaction pathways for
the DNA hole that are now well established (Bernhard and Close, 2004; Cai and Sevilla, 2004;
Sevilla and Becker, 2004; von Sonntag, 2006; Becker et al., 2007; Li and Sevilla, 2007; Becker
and Sevilla, 2008; Close, 2008; Kumar and Sevilla, 2008a). Instantaneously on ionization, holes
are formed on the bases and the sugar–phosphate backbone, in proportion to the electron density at
that site (see Scheme 19.1). Much work has focused on the hole in DNA because it is thought to be
the major damaging entity and this will be discussed in more detail in this chapter. In this section,
we present a brief overview. For the holes on the DNA bases, a fast hole-transfer process localizes
the hole preferentially to a nearby guanine base. Much work has established that stacks of Gs, that
is, GG, GGG, etc, are ultimately the most stable hole sites after long range hole transfer and these
G stacks form loci for DNA base damage (Arkin et al., 1997; Gasper and Schuster, 1997; Saito
et al., 1998; Núñez et al., 1999). The guanine hole itself is in a prototropic equilibrium between
the parent that is, the guanine cation radical (G
•+
), and its corresponding deprotonated species,
G(-H)
•
; however, G(-H)
•
is favored by several fold over G
•+
in double-stranded DNA owing to intra-
base pair proton transfer (Steenken, 1989, 1992, 1997; Adhikary et al., 2009; Kumar and Sevilla,
2009b). However, nucleophilic addition of water takes place only with G
•+
, forming the hydroxyl
adduct at C-8, that is, GOH
•
(Cullis et al., 1996; Shukla et al., 2004a, 2007). One-electron oxidation
and reduction of GOH
•
results in the molecular damage products 8-oxo-G and fapyG, respectively
(Ravanat et al., 2003; von Sonntag, 2006). These molecular products, 8-oxo-G and fapyG, are the
chief
products formed from the hole in DNA.
For
the sugar–phosphate backbone, hole transfer to a nearby DNA base competes with rapid
deprotonation from sugar to water. It is estimated that about 2/3 of the holes on the sugar group
transfer to the base (Swarts et al., 1992, 1996; Purkayastha et al., 2006a); the remaining holes
undergo deprotonation resulting in various neutral sugar radicals (C1′
•
, C3′
•
, C5′
•
) (Becker et al.,
2007; Becker and Sevilla, 2008; Kumar and Sevilla, 2008a). C3′
•
and C5′
•
further react to form
single strand breaks whereas C1′
•
leads to form unaltered base release sites (von Sonntag, 2006).
Although the C4′
•
is produced by the hydroxyl radical via the indirect effect, there is no evidence
at this time that direct type-effects of radiation produces this species in signicant quantities
(Razskazovskiy
et al., 2003a; Adhikary et al., 2006a).
19.1.2.2
reductive
p
athway,
o
ne-e
lectron a
dduct
Formation
Direct
ionization of DNA results in excess electrons that lose their kinetic energy, by energy transfer
to the surroundings, into molecular electronic and vibrational energy levels and, at lower energies,
into the phonon modes of the medium (Bernhard, 1981; Becker and Sevilla, 1993, 1998, 2008; Ward,
2000; Bernhard and Close, 2004; Sevilla and Becker, 2004; von Sonntag, 2006; Becker et al., 2007;
Li and Sevilla, 2007; Close, 2008; Kumar and Sevilla, 2008a). After thermalization, these electrons
add to DNA bases, preferentially at C and T (Bernhard, 1981; Becker and Sevilla, 1993, 1998, 2008;
Ward, 2000; Bernhard and Close, 2004; Sevilla and Becker, 2004; von Sonntag, 2006; Becker et al.,
2007; Close, 2008). Solvated electrons produced via the indirect effect also attach to the DNA bases
and result in the C and T anion radicals (Scheme 19.2) (O’Neill, 2001; von Sonntag, 2006). Solvated
and fully thermalized electron addition to DNA does not result in DNA strand breaks (O’Neill,
PhysicochemicalMechanisms of Radiation-Induced DNA Damage 507
HN
HN
H
2
N
H
2
C
OR
O
H
H
H
H
Base
OR
ht
H
2
N
H
2
N
N N
N
N
N
N
N
N
H
–H
+
8-oxo-dG
FapyG
–e
–
–e
–
+H
+
+e
–
OH
N
R
ht (excitation)
C1΄
•
R
R
G(OH)
•
H H
N
+
O O
O
+H
2
O
–H
+
–H
+
–H
+
+H
+
dRib
•
+
DNA
C3΄
•
C5΄
•
H
2
C
OR
O
H
H
H
H
Base
RO
HC
OR
O
H
H
H
H
H
Base
ssb and/or base
release
OR
G
•
+
G
•
+
A
•
+
C
•
+
T
•
+
G(–H)
•
•
•
•
•
•
•
sCheme 19.1 The one-electron loss pathway in DNA is depicted in this scheme. Sugar radicals are produced from direct ionization of the deoxyribose phosphate
(dRib)
backbone or excitation of the base cation radical. The symbols: ht, hole transfer; ssb, single strand break.
508 Charged Particle and Photon Interactions with Matter
2001; von Sonntag, 2006). After formation, the CandT anion radicals undergo protonation reac-
tions (Bernhard, 1981; Becker and Sevilla, 1993, 1998, 2008; Bernhard and Close, 2004; Sevilla and
Becker, 2004; von Sonntag, 2006; Becker et al., 2007; Close, 2008). For C, this is a fast reversible
protonation at the N3 position (pK
a
=13) and forT, a fast reversible protonation at O6 (pK
a
= 7)
(von Sonntag, 2006). Thus, the higher pK
a
for the C anion radical initially favors the stabilization
of the excess electron on C. Both C and T anion radicals or their reversibly protonated species also
undergo irreversible protonations at the C6 position (and also C5 for C) to form neutral carbon-
centered radical species (T(C6)H
•
and C(C6)H
•
), which on one-electron reduction form dihydrothy-
mine (DHThy) and dihydrocytosine (DHCyt) as molecular products (Scheme 19.2) (Bernhard, 1981;
Becker and Sevilla, 1993, 1998; von Sonntag, 2006). DHCyt is not stable as a molecular product and
slowly converts to dihydrouracil (DHUra) (von Sonntag, 2006). T(C6)H
•
and C(C6)H
•
have redox
potentials that allow them to oxidize other radical species and thus prone to the formation of the
dihydroproducts (von Sonntag, 2006). However, C(C5)H
•
is reducing to most species and this results
in its oxidation to form 5,6-dihydro 6-hydroxyl cytosine (von Sonntag, 2006).
Energetic electrons produced on or near DNA via direct-type effects can also add to DNA before
thermalization and solvation. Such species in the energy range 0–20eV are called low energy elec-
trons (LEE) (Boudaïffa et al., 2000; Bald et al., 2006, 2008; Simons, 2006; Swiderek, 2006; Liand
Sevilla, 2007; Kumar and Sevilla, 2008a; Sanche, 2008). LEE, possessing only 1–5eV have been
found to directly induce DNA single strand breaks whereas those with over 5eV have been found
to directly induce both single and double strand breaks in DNA (Boudaïffa et al., 2000; Bald et al.,
HN
HN
O
–
O
O
O
N
N
dR
N
O
dR
N
N
H
H
H
dR
T(C6)H
•
O
O
H
Base
–
O
O
–
O
O
P
+
+
H
H
H
H
H
2
C
OR
ssb
LEE
DNA
et
T C
N
dR
C(N3)H
•
DHThy
DHcyt
CH
3
NH
2
NH
2
–NH
3
+H
2
O
DHUra
CH
3
DNA
•
–
+e
–
+e
–
+e
–
T
•
–
+H
+
+H
+
+H
+
+H
+
–H
+
O
H
Base
H
H
O
O
O
–
P
H
H
H
2
C
OR
O
H
Base
H
H
O
H
H
H
2
C
O
–
C3
΄
•
ROPO
2
–
•
G
•
–
A
•
–
C
•
–
C
•
–
T
•
–
•
•
•
•
•
•
dephos
sCheme 19.2 The reductive (one-electron addition) pathway in DNA is depicted in this scheme.
Thermalized electrons add to the DNA bases and transfer to thymine and cytosine bases, where they
undergo reversible and irreversible protonation reactions. Strand cleavage and sugar phosphate radicals
are not produced by thermalized electrons, however, low energy electrons (LEE) with energies from 1 to
20 eV produced from direct ionization do cleave the DNA backbone, yielding radical species. The symbols:
et,electron transfer; ssb, single strand break.
PhysicochemicalMechanisms of Radiation-Induced DNA Damage 509
2006, 2008; Simons, 2006; Sanche, 2008). The mechanism of formation has been a focus of active
interest (Boudaïffa et al., 2000; Bald et al., 2006, 2008; Simons, 2006; Swiderek, 2006; Li and
Sevilla, 2007; Kumar and Sevilla, 2008a; Sanche, 2008). The two radicals likely to be formed by
electron fragmentation of the DNA sugar–phosphate backbone,
C
dephos
′
3
i
and
ROPO
2
− i
, have both
been observed in ion-beam irradiated DNA samples and were attributed to LEE effects (Scheme19.2)
(Beckeretal., 1996, 2003; Becker and Sevilla, 1998; Sevilla and Becker, 2004; Becker et al., 2007;
Becker and Sevilla, 2008). ESR studies estimated that the production of the carbon-centered radical
C
dephos
′
3
i
dominates by 20-fold over the phosphorous radical (
ROPO
2
−i
) (Becker et al., 1996, 2003).
This result is in agreement with the cleavage products found in product analyses studies by Sanche
and coworkers (Sanche, 2008). However, the fact that the formation of these strand-break radicals is
found to be 10-fold lesser by low LET radiation than high LET radiation suggests that energy density
is a critical factor in the formation of these radicals (Becker et al., 1996, 2003). It is possible that the
electronic and vibrational excitations coupled with thermalized electrons or even electron adducts
to DNA bases may induce strand cleavage (Li and Sevilla, 2007; Kumar and Sevilla, 2008a). The
two sugar–phosphate backbone radicals,
C
dephos
′
3
i
and
ROPO
2
−i
, clearly and directly result from
strand fragmentations without further chemistry. The
C
dephos
′
3
i
radical is likely to react further by
beta phosphate cleavage to remove one additional base from its strand (Becker et al., 1996, 2003).
19.2 pathways in direCt-type eFFeCts
19.2.1 dna holeS (electron loSS) trapped radicalS after
l
ow let irradiation at low teMperatureS
19.2.1.1 radicals Found after irradiation at 77 k
This portion of the chapter focuses on those radiation-produced entities that can be detected by ESR
spectroscopy, that is, free radicals. After irradiation of hydrated salmon sperm DNA at 77K, the
ESR spectrum obtained consists of a composite spectrum of mainly eight free radicals on the DNA
bases: G
•+
, T
•−
, and C(N3)H
•
; and on the sugar–phosphate backbone, C1′
•
, C3′
•
, C5′
•
,
C
dephos
′
3
i
, and
RO
2
PO
•−
(Schemes 19.1 and 19.2) (Wang et al., 1994; Shukla et al., 2005; Becker et al., 2007; Becker
and Sevilla, 2008). Of these, four are from the electron loss (oxidative) path, G
•+
, C1′
•
, C3′
•
, and C5′
•
(Scheme 19.1), and the remaining four from the electron-gain (reductive) path, T
•−
, C(N3)H
•
,
C
dephos
′
3
i
, and RO
2
PO
•−
(Scheme 19.2). It is possible, using proper benchmark spectra, to analyze the com-
posite spectra found for the amount of each radical present (Table 19.1). The relative G-values are
estimated
to have an error limit of ±10%.
table 19.1
radicals
Found in dna
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