You are on page 1of 4

commentary

symptoms in children from ISAAC Phase Three.


J Allergy Clin Immunol 124:12518.e23
Schmitt J, Langan S, Williams HC (2007) What
are the best outcome measurements for atopic
eczema? A systematic review. J Allergy Clin
Immunol 120:138998
Schmitt J, Langan S, Stamm T et al. (2011) Core
outcome domains for controlled trials and
clinical recordkeeping in eczema: international
multiperspective Delphi consensus process.

J Invest Dermatol 131:62330


Tugwell P, Boers M, Brooks P et al. (2007)
OMERACT:
an
international
initiative
to improve outcome measurement in
rheumatology. Trials 8:38
Vartiainen E, Petays T, Haahtela T et al. (2002)
Allergic diseases, skin prick test responses,
and IgE levels in North Karelia, Finland, and
the Republic of Karelia, Russia. J Allergy Clin
Immunol 109:6438

See related article on pg 753

Prospects for Skin Cancer Treatment


and Prevention: The Potential
Contribution of an Engineered Virus
Jennifer A. Cafardi1, Rubina Shafi1,2, Mohammad Athar13 and
Craig A. Elmets14
Nonmelanoma skin cancers are among the most common human malignancies.
Although typically not lethal, they are responsible for tissue deformity and
substantial morbidity, particularly in high-risk populations. Solar UVB radiation
a major etiologic factor for this kind of malignancyproduces DNA lesions such
as cyclobutane pyrimidine dimers and 6-4 photoproducts in skin. These lesions
are removed through nucleotide excision repair because humans lack a DNA
glycosylase required to initiate base excision repair of pyrimidinepyrimidine
photoproducts but produce all the other proteins required for this process. In this
issue, Johnson et al. show that a DNA glycosylase derived from Chlorella virus and
engineered to enhance tissue penetration and nuclear localization can remove
UVB-induced DNA lesions in a human skin equivalent model and that the protein
can be incorporated into a topical formulation for the prevention and treatment
of UVB-induced DNA damage. These results suggest that such an enzyme may be
incorporated into regimens for the chemoprevention of skin cancers.
Journal of Investigative Dermatology (2011) 131, 559561. doi:10.1038/jid.2010.394

When UVR interacts with skin, it


produces photochemical changes in
DNA that can adversely affect the skins
biological activities and produce disease.
Two lesions most commonly result from
UVR exposure: cyclobutane pyrimidine
dimers (CPDs), in which adjacent
pyrimidine rings are coupled through
carboncarbon double bonds at the 5
and 6 positions, and 6,4-pyrimidine
pyrimidone photoproducts, in which

adjacent pyrimidines are connected


through a single bond between the 6
position of one molecule and the 4
position of the other. These alterations,
if not restored to their original state,
produce mutations that can ultimately
lead to nonmelanoma skin cancers
(NMSCs), including both squamous
cell (SCCs) and basal cell carcinomas
(BCCs) (Cleaver and Crowley, 2002).
Fortunately, virtually all living organisms

Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama, USA; 2UAB


Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, Alabama, USA;
3
UAB Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA
and 4Birmingham VA Medical Center, Birmingham, Alabama, USA
1

Correspondence: Craig A. Elmets, Department of Dermatology, University of Alabama at Birmingham,


1530 3rd Avenue South, Birmingham, Alabama 35294, USA. E-mail: celmets@uab.edu

possess intricate repair mechanisms


to mend damaged DNA. Bulky lesions
such as CPDs are normally repaired by
nucleotide excision repair, but they can
also be restored by base excision repair
(BER). Humans, however, can repair
CPDs only through nucleotide excision repair (NER). Although human cells
have most of the enzymes necessary to
complete BER, they lack an important
DNA glycosylase required to initiate
the process (Cafardi and Elmets, 2008).
The importance of DNA repair for protection from UV-induced skin cancers
is evident if one examines individuals
who suffer from xeroderma pigmentosum (XP), an inherited disease in which
the NER pathway of DNA is deficient.
These patients have a propensity to
develop extensive photodamage, cutaneous SCCs, BCCs, and melanomas at
an unusually early age.
Even in healthy individuals NMSCs
are particularly common. In the United
States alone, the estimated 1.53.5 million new NMSC diagnoses each year
exceed those of all other types of cancer
combined. Although rarely lethal, these
lesions are locally destructive and the
cost of their removal represents an economic burden to the healthcare system.
The direct cost for treatment of NMSCs
in the United States was estimated to be
$1.5 billion in 2004, and if actinic keratosespremalignant lesions that may
progress to SCCswere included, the
direct cost would increase to over $2.3
billion (Bickers et al., 2006). In contrast
to most other malignancies, in which
the incidence has stabilized or declined,
the rate of NMSCs continues to rise
(Athas et al., 2003; Karagas et al., 1999).
Moreover, in a population-based retrospective study from 1976 to 2003, the
incidence of BCCs and SCCs in patients
under 40 years old was found to be
increasing significantly (Christenson et
al., 2005).
Efforts to prevent actinic keratoses and
NMSCs have been directed at counseling
patients to limit the amount of UVR that
reaches the skin, either through avoidance of sun exposure and tanning bed use
or through the application of sunscreens.
The American Academy of Dermatology,
the American Cancer Society, and other
organizations throughout the world have
developed sophisticated educational
www.jidonline.org 559

commentary

Clinical Implications
Cv-pdg-NLS-TAT is a genetically engineered glycosylase that enables
human skin to perform base excision repair of UVR-damaged DNA.
In contrast to other topically applied enzymes, Cv-pdg-NLS-TAT has
greater nuclear localization, can penetrate into the lower levels of the
epidermis without encapsulation into a delivery vehicle, is more stable,
and may act against a wider variety of UVR-induced mutations.
Cv-pdg-NLS-TAT shows promise as a topical preventive and therapeutic
agent for patients at high risk for UVR-induced skin cancer.

materials to inform the public of the


deleterious effects of excessive UVR
exposure and how to prevent them.
Unfortunately, these campaigns have met
with varying degrees of success.
Chemoprevention, the prevention of
cancer through dietary manipulation or
pharmacological intervention, represents an alternative to sun avoidance and
the application of sunscreens for inhibiting skin cancer. Because chemopreventive agents are administered chronically
to healthy individuals, emphasis must be
placed not only on efficacy but also on
the absence of serious side effects. The
ideal chemopreventive agent would be
characterized by (i) little or no toxicity,
(ii) high efficacy, (iii) easy administration, (iv) a known mechanism of action,
and (v) acceptance of its use by individuals at risk for cancer. Preclinical and
clinical evaluations of chemoprevention
drugs differ substantially from those of
chemotherapeutic agents (Mukhtar and
Agarwal, 1996).
Drugs that target DNA damage or its
repair fulfill many of the criteria of the
ideal chemopreventive agent, and they
have attracted particular attention. For
example, the bacteriophage T4 pyrimidine dimer-specific DNA glycosylase
(T4-PDG), also known as T4 endonuclease V (T4N5), enhances DNA repair
and reduces the frequency of UV-induced
mutations in epidermal keratinocytes.
Liposome-encapsulated T4N5 applied
to human skin in vivo can be detected in
keratinocytes, where it initiates repair of
UV-induced DNA damage through BER.
In a phase II clinical trial, patients with XP
treated with liposome-encapsulated T4N5
for one year showed a marked reduction
in actinic keratoses and BCCs as compared with those treated with placebo
(Yarosh et al., 2001). As mentioned pre-

viously, patients with XP have a defect


in DNA repair, unlike most individuals
who develop NMSCs, and the efficacy
of T4N5 has not yet been determined in
DNA repair-proficient individuals.
Photolyase is an enzyme derived from
the algae Anacystis nidulans. Following
activation by visible light, photolyase
unlinks CPDs and 6-4 pyrimidine pyrimidone photoproducts, restoring them
to their native conformation (Li et al.,
2010). Application to UVB-irradiated
skin in vivo in a liposomal preparation
followed by activation with photoreactivating light also led to a reduction in
CPDs (Stege et al., 2000).
In this issue, Johnson et al. report a
novel enzyme that enhances the repair
of UV-damaged DNA: pyrimidine dimer
glycosylase, expressed by the Chlorella
virus (Cv-pdg). Because the enzyme
localizes primarily in the cytoplasm rather
than in the nucleus and because it would
not be expected to penetrate through the
stratum corneum when applied topically,
the investigators incorporated a nuclear
localization signaling sequence (NLS) and
a membrane permeabilization peptide
(TAT) into the molecule. The modified enzyme is particularly interesting
because the engineered structure allows
for its effective penetration through the
top layers of the skin without the need
for encapsulation into a delivery vehicle.
Cv-pdg contributes to BER in prokaryotic
species and is similar to the one lacking
in human cells. In the study, Cv-pdg-NLSTAT was applied topically to human skin
equivalents. The engineered enzyme was
absorbed and reached the basal layer of
the epidermal equivalent. There, it localized in the nucleus and was found to be
effective at diminishing a high percentage of CPDs when administered either
before or after exposure to UVR.

560 Journal of Investigative Dermatology (2011), Volume 131

These findings suggest that Cv-pdgNLS-TAT may have both cancer preventive and therapeutic applications and
therefore could be ideal for individuals
at high risk for NMSCs, such as patients
with XP, organ transplant recipients, and
individuals with extensive photodamage. However, evidence of clinical efficacy and tolerability for Cv-pdg-NLS-TAT
awaits clinical trials. That Cv-pdg-NLSTAT did not require encapsulation into
a delivery vehicle to reach basal keratinocytes is an advantage over both
T4N5 and photolyase. The Cv-pdg-NLSTAT topical enzyme also is more stable
over a range of salt concentrations and
temperature extremes than other topical
formulations that accelerate the repair of
UV-damaged DNA (McCullough, 1998).
Furthermore, Cv-pdg-NLS-TAT showed
favorable retention kinetics in skin cells,
indicating that it may be ideal for developing a convenient dosing regimen for
human application.
Although mutations in the Sonic
hedgehog pathway (for BCCs) and in p53
(for both BCCs and SCCs) are responsible
for most NMSCs, some of those tumors
lack these mutations (Athar et al., 2006).
Because Cv-pdg-NLS-TAT is able to
repair a broad range of DNA mutations,
Johnson et al. (2011) postulate it could
have broad efficacy against a variety of
UV-induced mutations and, in contrast to
other potential chemopreventive agents
(Hacker et al., 2010), may be effective for
the small number of UV-induced tumors
without CPDs. Cv-pdg-NLS-TAT may
also be useful in melanoma prevention
because it has broad substrate specificity
and an improved nuclear concentration
caused by the NLS component.
Even if Cv-pdg-NLS-TAT is found to be
effective, additional properties remain to
be evaluated for it to be acceptable for
widespread application in humans,
including examination of its irritancy
following chronic application and its
cosmetic elegance.
Another important issue is the effect
of this enzyme on the repair of oxidative
DNA lesions induced by the reactive
oxygen species that arise following UV
exposure. UVB and UVA radiation can
lead to oxidative DNA damage, such as
8-hydroxyguanisine, which is mutagenic
and may contribute to the development
of skin cancers (Kunisada et al., 2005;

commentary

Montaner et al., 2007). It would be


interesting and important to determine
whether
Cv-pdg-NLS-TAT
repaired
this type of DNA damage as well. This
enzyme may not have a direct effect on
the repair of oxidative DNA damage, but
it may contribute to an overall upregulation of repair mechanisms in the nuclear
environment.
Because NMSCs continue to be a
major health and economic issue, the
development of new treatment and preventive modalities is crucial. In addition to standard recommendations such
as sun avoidance and the application
of sunscreen, there are promising treatments and preventive therapies on the
horizon. Cv-pdg-NLS-TAT may be one
such modality; future clinical studies will
further define its efficacy and tolerability.
CONFLICT OF INTEREST

The authors state no conflict of interest.

ACKNOWLEDGMENTS

The research work of the authors is supported


by National Institutes of Health (NIH) grant R01
ES015323 (M.A.), Veterans Administration grant
18-103-02 (C.A.E.), and NIH grants P30 CA013148
and P30 AR050948.

references

Athar M, Tang X, Lee JL et al. (2006) Hedgehog


signalling in skin development and cancer.
Exp Dermatol 15:66777
Athas WF, Hunt WC, Key CR (2003) Changes in
nonmelanoma skin cancer incidence between
19771978 and 19981999 in Northcentral
New Mexico. Cancer Epidemiol Biomarkers
Prev 12:11058
Bickers DR, Lim HW, Margolis D et al. (2006) The
burden of skin diseases: 2004: a joint project
of the American Academy of Dermatology
Association and the Society for Investigative
Dermatology. J Am Acad Dermatol 55:490
500
Cafardi JA, Elmets CA (2008) T4 endonuclease
V: review and application to dermatology.
Expert Opin Biol Ther 8:82938
Christenson LJ, Borrowman TA, Vachon CM et al.
(2005) Incidence of basal cell and squamous
cell carcinomas in a population younger than
40 years. JAMA 294:68190
Cleaver JE, Crowley E (2002) UV damage, DNA
repair and skin carcinogenesis. Front Biosci
7:d102443
Hacker E, Muller HK, Hayward N et al. (2010)
Enhancement of DNA repair using topical T4
endonuclease V does not inhibit melanoma
formation
in
Cdk4(R24C/R24C)/TyrNras(Q61K) mice following neonatal UVR.
Pigment Cell Melanoma Res 23:1218
Johnson JL, Lowell BC, Ryabinina OP et al.
(2011) TAT-mediated delivery of a DNA repair

enzyme to skin cells rapidly initiates repair of


UV-induced DNA damage. J Invest Dermatol
131:75361

AP lyase from a eukaryotic algal virus,


Paramecium bursaria chorella virus-1. J Biol
Chem 273:13136-42

Karagas MR, Greenberg ER, Spencer SK et al.


(1999) Increase in incidence rates of basal
cell and squamous cell skin cancer in New
Hampshire, USA. New Hampshire Skin
Cancer Study Group. Int J Cancer 81:5559

Montaner B, ODonovan P, Reelfs O et al. (2007)


Reactive oxygen-mediated damage to a
human DNA replication and repair protein.
EMBO Rep 8:10749

Kunisada M, Sakumi K, Tominaga Y et al. (2005)


8-Oxoguanine formation induced by chronic
UVB exposure makes Ogg1 knockout mice
susceptible to skin carcinogenesis. Cancer
Res 65:600610
Li J, Liu Z, Tan C et al. (2010) Dynamics and
mechanism of repair of ultraviolet-induced
(6-4) photoproduct by photolyase. Nature
466:88790
McCullough AK, Romberg MT, Nyaga S et al.
(1998) Characterization of a novel cis-syn and
trans-syn-II pyrimidine dimer glycosylase/

Mukhtar H, Agarwal R (1996) Skin cancer


chemoprevention. J Investig Dermatol Symp
Proc 1:20914
Stege H, Roza L, Vink AA et al. (2000) Enzyme
plus light therapy to repair DNA damage in
ultraviolet-B-irradiated human skin. Proc Natl
Acad Sci USA 97:17905
Yarosh D, Klein J, OConnor A et al. (2001)
Effect of topically applied T4 endonuclease
V in liposomes on skin cancer in xeroderma
pigmentosum:
a
randomised
study.
Xeroderma Pigmentosum Study Group.
Lancet 357:9269

See related article on pg 779

Peeling Skin Syndrome:


Genetic Defects in Late Terminal
Differentiation of the Epidermis
Paul E. Bowden1
In this issue, Israeli and colleagues confirm that homozygous mutations in
corneodesmosin (CDSN) cause type B peeling skin syndrome (PSS), an autosomal
recessive skin disorder. The deletion mutation described resulted in a frameshift, producing a downstream premature stop codon and early truncation of the
protein. The recently described CDSN nonsense mutation in another PSS family
also resulted in protein truncation and nonsense-mediated mRNA decay. Type B
generalized PSS can now be clearly distinguished from acral PSS, caused by mutations in transglutaminase 5. This directly affects cornified envelope cross-linking
rather than corneodesmosome adherence. These observations provide new
insight into the molecular defects underlying two closely related forms of PSS.
Journal of Investigative Dermatology (2011) 131, 561564. doi:10.1038/jid.2010.434

PSS

Peeling skin syndrome (PSS), first


described in the early twentieth century
(Fox, 1921), is a rare cutaneous genodermatosis that is classified into two
forms: acral PSS (APSS; OMIM 609796)
and generalized PSS (OMIM 270300).

Although it has been suggested (Traupe,


1989) that the generalized form can
be further subdivided into noninflam
matory (type A) and inflammatory
(type B), other phenotypes including
those with hair and nail abnormal
ities have also been described, further

Department of Dermatology and Wound Healing, School of Medicine, Cardiff University, Heath Park,
Cardiff, UK

Correspondence: Paul E. Bowden, Department of Dermatology and Wound Healing, School of


Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. E-mail: bowden@cardiff.ac.uk

www.jidonline.org 561

Copyright of Journal of Investigative Dermatology is the property of Nature Publishing Group and its content
may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express
written permission. However, users may print, download, or email articles for individual use.