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Chapter 112

Ultraviolet Radiation
Masaoki Kawasumi & Paul Nghiem


Ultraviolet Radiation-Induced
DNA Damage and Repair
Both UVB and UVA can be absorbed by cytoplasmic
ring-containing molecules such as NADH (reduced
form of nicotinamide-adenine dinucleotide),
riboflavin, quinones, tryptophan and tyrosine, and
the heme group of catalase (see Chapter 90). The
resulting energetic molecule can interact with DNA
to produce a T-containing cyclobutane dimer90 or
can produce reactive oxygen species. In the latter
pathway, the chromophores energy is transferred
to oxygen, resulting in singlet oxygen (1O2) or, if
an electron is transferred, superoxide (O2). In the
presence of water, these lead to hydrogen peroxide (H2O2) and thence, in the presence of Fe2+, the
hydroxyl radical (OH). Hydroxyl radicals produce
oxidative DNA damage resembling that after
radiation.91 Reactive oxygen species react with lipid
membranes and the redox-sensitive catalytic site of
phosphatases (see Section Cytoplasmic Signaling).
Their production of 8-hydroxy-2-deoxyguanosine
(8-OHdG; eFig.112-1.1B) in DNA probably accounts
for the occasional non-UVR-like mutations after
UVB. UVR also upregulates nitric oxide (NO), a more
stable radical species that can participate in similar
reactions after diffusing long distances and traversing lipid membranes.92
Nucleotide excision repair (NER; see Chapter 110)
is the key protection mechanism against the lethal
and mutagenic effects of UVR-induced cyclobutane
dimers and (64) photoproducts. Two NER pathways have been identified, global genome repair
(GGR) and transcription-coupled repair (TCR).93
GGR removes DNA lesions throughout the genome,
whereas TCR is specialized for DNA lesions in the
transcribed strand of transcriptionally active genes.
In humans, excision repair requires the concerted

action of six repair factors (XPA, RPA, XPC, TFIIH,

XPG, and XPF-ERCC1) composed of nearly 20 polypeptides, some identified and named according to
the seven complementation groups of xeroderma
pigmentosum (XP). The enzymatic steps of NER
include: (1) recognizing damaged DNA, (2) forming
dual incisions that bracket the UV lesion, (3) removing the damaged oligomer (2432 nucleotides in
length), (4) gap filling by DNA synthesis, and (5)
ligating the repaired strand.94 GGR is considered
error-free because the complementary undamaged
strand is used as a template for repair synthesis.
This core machinery of GGR is also used by TCR
in active genes. Whereas in GGR the XPC protein
recognizes distortions in the DNA double helix,
the damage recognition signal for TCR is an RNA
polymerase II complex stalled at a UV lesion, which
attracts the core GGR machinery. RNA polymerase
II sterically hinders the accessibility of NER factors
and is therefore removed from the damage site
by the CSA and CSB proteins. CSA and CSB are the
genes mutated in Cockaynes syndrome, an autosomal recessive disorder characterized by cutaneous
photosensitivity and physical and mental retardation.95 Induction of these repair factors is genetically
regulated (see Section DNA Damage Signaling).


DNA Damage Signaling
(See Chapter 110)
A cell with damaged DNA upregulates normal p53
protein.145,146 UV signaling is initiated by cyclobutane dimers and (64) photoproducts specifically
in the small minority of actively transcribed genes,
with stalled RNA polymerase both recruiting excision repair proteins and initiating signaling.6,7 In an
unknown way, this activates ATR and CHK1 kinases,
which phosphorylate p53 at sites that make it
resistant to proteasomal degradation mediated by
HDM2 (MDM2 in mouse). p53 then transcriptionally
activates a large repertoire of genes, including the
repair proteins p48, which is required for GGR and
is defective in XP group E, and GADD45. Additionally, p53 functions as a chromatin accessibility
factor, modifying the structure of damaged DNA
and making it more accessible to repair factors.
p53 also transactivates the cell cycle arrest protein
p21, although in keratinocytes UVR induces p21

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156 Chapter 112: Ultraviolet Radiation Carcinogenesis

even without p53.147 UVR primarily slows down S

phase (S phase delay) and induces a modest G2
arrest, unlike ionizing radiation, which uses p53
to induce G1 arrest. It is often said that cell cycle
arrest facilitates DNA repair and survival, but there
is little evidence supporting this concept; deleting
the p21 cell cycle arrest protein has no effect on
repair after UVR exposure.148 These guardian of the
genome roles of p53 are complemented by a cellular proofreading role in which p53 erases aberrant cells by apoptosis rather than repairing them:
it transcriptionally activates the death receptor Fas
and proapoptotic effectors Bax (Bcl-2associated
X protein), Bak, Bid, and PUMA; it directly activates
Bax protein at the mitochondrion; and it inactivates E2F1, which otherwise inhibits antiapoptotic
Bcl-2.8 This suite of UV responses is lost when p53
is mutated by sunlight. DNA damage also activates
the cytoplasmically sequestered transcription factor nuclear factor B (NFB), which then activates
proinflammatory cytokines such as interleukin
10, growth signals, and antiapoptotic signals.149,150
Finally, DNA photoproducts trigger UVR-induced
systemic immunosuppression and suppression of
dendritic cell antigen-presenting activity, but do
not contribute to inflammatory edema.151,152

Cytoplasmic Signaling
The UV response initially referred to the p53independent activation of JNK, its target c-JUN, and,
via the FOS-JUN transcription factor AP-1, induction of genes for collagenase, metallothionein, and
c-JUN and c-FOS themselves.153 The signal begins
when reactive oxygen species generated by UVB or
UVA photosensitization inactivate phosphatases by
converting a highly sensitive cysteine residue in the
catalytic site to sulfenic acid.154,155 Dephosphorylation of growth factor receptor dimers and death
receptor trimers is slowed, leading within minutes
to more phosphorylated active receptors. Activated
death receptors (involved in apoptosis) such as
Fas and tumor necrosis factor- (TNF-) receptor
then cluster even without a ligand, recruiting the
adapter proteins DAXX and FADD, and activating
cytoplasmic kinases and scaffold proteins.156161
These activate ASK1 and MEKK4/7 kinases and their
target, JNK.162 Phosphatase inhibition can activate
JNK directly. In parallel, AP-1 also induces genes for
the death receptor ligands, FasL and TNF-.163165
These ligands, together with UV upregulation of
FAS receptor via p53,166 create a delayed feedback
loop that, as with ionizing radiation,167 appears to
prolong the rapid but transient response triggered

by UVRs inactivation of phosphatases. Without

this prolongation, UVR-activated NFB quickly
terminates the JNK response.168,169 This loop is
important because transient JNK activation leads
to cell proliferation, but constitutive JNK activation
induces apoptosis.170,171 AP-1 also induces immunomodulatory cytokines such as interleukin 12,
which facilitates NER172; the AP-1-induced metalloproteinases degrade dermal extracellular matrix
molecules, such as collagen, and may contribute to
photoaging.173 UVR also blocks initiation of protein
translation, via kinases that inactivate elongation
factor eIF2.174

Ultraviolet Radiation
Wavelength and Carcinogenesis
Showing causality requires manipulating an experimental system, which usually cannot be done
in humans. Early experiments generated fibrosarcomas by irradiating mouse ears. SCCs can be
generated by irradiating back skin daily for about
4 months with doses of UVB severalfold above the
minimal erythemal dose. The sequence of events
resembles that in humans, with p53-mutant clones
appearing early, followed by reddish lesions that
resemble AKs both visibly and histologically.226,227
SCCs induced by UVB contain UV signature p53
mutations.228 p53-mutant clones may be a precursor
lesion for SCC.229,230 Growth of an existing SCC no
longer depends on UVR.227,231
The action spectrum for carcinogenesis in the hairless mouse closely approximates that for erythema
in human skin and edema in murine skin, with the
most effective wavelengths at 295305 nm in the
UVB region.232,233 Calculations show that this peak
is the product of the 260-nm DNA absorption peak
and absorption by the skin.45 Activity decreases
sharply at wavelengths above this range. The UVA
used in tanning beds can also cause skin tumors in
mice47; p53 mutations are rare in this setting.234
UVB acts as both initiator and promoter for mouse
skin papillomas,235,236 and UVA acts as a promoter.237
Tumor promoters are agents that increase the
frequency of tumors, but only when delivered after
the initiator mutagen and only while the promoter
is present.238 Initiation is considered to contribute irreversible genetic events, whereas promotion stim-

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Chapter 112:

ulates reversible growth acceleration. The promotion concept developed from studies of chemically
induced papillomas, especially those now known to
be mutated at Hras and at low risk for conversion to
SCCs, which are transiently increased after treating
with a chemical such as phorbol ester.239 Similarly,
90% of UVB-initiated p53-mutant clones regress
within 3 weeks after UVB is terminated; T or B cells
are not required.199,200,240 Because it is now clear that
tumorigenesis consists of multiple cycles of mutation and growth, dividing cancer development into
initiation and promotion phases has been largely
superseded by a focus on the timing of specific
genetic and cellular mechanisms.
Studies in mice also revealed that: cyclobutane
dimers are responsible for UVB-induced apoptosis, hyperplasia, p53-mutant clones, and SCC241;
repairing the UVB-induced oxidative lesion 8-OHdG
reduces SCC by one-half242; p53/ mice are highly
susceptible to UVR-induced AK and SCC,243,244
whereas UVR induces BCC in Ptch+/ mice245; and
basaloid budding and BCC can be induced by
overexpressing the hedgehog pathway.190,246,247
Physiologic status also affects tumor development:
exposure to stress (fox urine) reduces the latency of
UVR-induced SCC from 21 weeks to 8 weeks.248
Defects in DNA damage repair have been widely
investigated, with XP in particular showing an
increased predisposition to UV-induced skin cancer
development (see Chapter 110). Mice lacking the
vitamin D receptor also showed decreased repair
of photolesions, suppressed apoptosis, and high
susceptibility to UV-induced skin cancers, suggesting that the vitamin D receptor may play a role
in DNA repair and thus be protective against UV
carcinogenesis.249 Deficiency of IL-12 (an important mediator of inflammation and an inducer of
DNA repair) suppresses repair of UV-induced DNA
lesions, exacerbates inflammatory responses, and
enhances UV-induced tumor development.250

Ultraviolet Radiation Carcinogenesis 157

papillomas and SCCs but no melanomas. Generating melanomas in mice is also attempted by
genetic manipulation. Ocular and dermal melanomas arise without UVR when the SV40 virus early
region sequences are put under the control of the
tyrosinase promoter.255 When the metallothionein
promoter drives hepatocyte growth factor, melanocytes are produced in the epidermisnot their
normal location in miceand a single high dose
of sunlamp UVR in the neonate, but not adult,
generates melanomas months later.256 When the
tyrosinase promoter is used to drive mutant HRAS
in a mouse deleted for the ARF gene, melanomas
arise months later but sooner if the mice receive a
single high neonatal UVR dose.257 One-half the UVRinduced tumors carry amplified CDK6, reminiscent
of CSD melanomas in humans. It is crucial to realize,
however, that both metallothionein and tyrosinase
promoters are UVR-inducible,258260 so the single
UVR dose used here is unlikely to model the role of
UVR in causing human melanoma.

Immune Function and Skin Cancer

The mouse model reveals an important immunologic component to tumor progression. Murine
UVR-induced tumors are highly immunogenic, but
early in the course of chronic UVR, before primary
tumors are evident, mice lose their ability to reject
UVR-induced tumors.261 Therefore, UVR has a
systemic immunosuppressive effect. Natural killer
T lymphocytes are the suppressor T cells responsible.262

Modeling melanoma has been more challenging. A melanoma-susceptible fish demonstrated

the ability of UVA-induced reactive oxygen to
induce melanomas.251 In the opossum Monodelphis
domestica, UVB + UVA induces melanomas and
melanocytic hyperplasia, and UVA can itself induce
melanocytic hyperplasia.252,253 In hairless mice, a
single application of DMBA (7,12-dimethylbenz[a]
anthracene) as an initiator and subsequent thriceweekly exposures to either UVB, UVA, or UVB + UVA
resulted in the development of melanoma.254 Mice
that received DMBA alone or UVR alone developed

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