The Werner syndrome protein:
an update
Junko Oshima
Summary
Progeria and progeroid syndromes are characterized by
the earlier onset of complex senescent phenotypes.
WRN
was originally identified as a gene responsible for
Werner syndrome (WS; ``Progeria of Adults''). The
WRN
gene product has RecQ-type helicase domains in the
central region of the protein. Subsequent studies also
revealed that the WRN protein displays exonuclease
activity and acts as a transcriptional activation factor.
These biochemical studies, combined with cell biologi-
cal studies, suggested that this protein is likely to be
involved in the response to DNA damage during
replication, as well as recombination and transcription
processes. However, the precise molecular mechanisms
by which mutations in
WRN
cause the WS phenotype
remain unknown. Recent progress in the understanding
of the WRN protein and its implication in the normal
aging process are discussed. BioEssays 22:894±901,
2000. ß 2000 John Wiley & Sons, Inc.
Introduction
Over the last several years, understanding of human RecQ
helicase-deficient disorders has increased considerably. To
date, there are five known human RecQ helicases: RecQL,
(1)
WRN,
(2)
BLM,
(3)
RecQ4
(4)
and RecQ5
(4)
(Fig. 1). Mutations in
helicase genes are believed to be responsible for genomic
instability syndromes. In fact, mutations in the RecQ
helicases WRN, BLM and RecQ4 genes have been shown
to be responsible for the autosomal recessive disorders
known as Werner syndrome (WS), Bloom syndrome (BS),
and Rothmund Thomson syndrome (RTS),
(5)
respectively.
For each of the three identified human diseases associated
with RecQ helicases, premature aging is a strong accom-
paniment. WS is characterized by the aged appearance and
common age-related disorders in their middle ages.
(6±8)
The
hallmark of BS cells is a high frequency of sister chromatid
exchanges, and BS patients show sun-sensitive skin pig-
mentation and a predisposition to malignancies.
(9)
Main
clinical features of RTS include poikilodermatous skin
changes and a predisposition to malignancies, particularly
osteosarcomas.
(10)
Human diseases caused by mutations in
the RecQL and RecQ5 have not been reported. One unique
feature of the WRN protein is that it functions both as a
helicase and as an exonuclease. It is not clear how these two
functions are coupled during DNA metabolism.
The mechanism by which mutations in WRN cause the
WS phenotypes remains to be established. Here, biochem-
ical studies investigating the function of the WRN protein will
be reviewed. Further cellular defects present in WS patients
will be discussed, with an emphasis on the differences
between normal aging and WS cells.
Clinical characteristics of Werner syndrome
WS was first described by Dr Otto Werner at the Kiel
University, in 1904.
(11)
Individuals with the WRN null
mutations prematurely develop an aged-appearance and
age-related disorders including graying of the hair, hair loss,
tight skin, cataracts, diabetes mellitus, hypogonadism, osteo-
porosis, atherosclerosis and cancers.
(6±8,12)
The average
age of clinical diagnosis of this syndrome is in the late thirties
and death usually occurs before the age of 50 due to cancer
or vascular diseases such as atherosclerosis (both myocar-
dial and cerebrovascular). The prevalence of heterozygotes
is expected to be higher than 0.6% in Japan, which has the
highest frequency of reported WS cases.
(13)
The frequencies
of the WRN mutation in non-Japanese populations are not
known. The chronology of symptoms appears to be similar
between Caucasian and Japanese WS patients.
(6,8)
Symptoms of some aging disorders, such as Hutchinson-
Gilford progeria, may start to develop as early as infancy.
(14)
In contrast, WS patients develop normally initially but lack the
pubertal growth spurt during adolescence, a symptom often
recognized only retrospectively. Several features distinguish
WS from the normal aging process. For example, ratios of
mesenchymal:epithelial cancers in WS is approximately 1:1,
as compared to 1:10 in the normal aging population.
(15)
WS
patients usually do not develop Alzheimer-type dementia.
(16)
Werner syndrome gene product
The WRN gene consists of 35 exons that encode a protein of
1,432 amino acids (Fig. 2).
(17)
The calculated molecular mass
of the gene product is 163 kDa; however, western blot
analysis revealed a single band of approximately 180 kDa.
Structural analysis of the WRN protein suggested that the
894 BioEssays 22.10 BioEssays 22:894±901, ß 2000 John Wiley & Sons, Inc.
Department of Pathology, Box 357470, HSB K-543. University of
Washington, 1959 NE Pacific Ave., Seattle, WA 98195-7470. E-mail:
picard@u.washington.edu
Funding agencies: National Institute of Aging; National Cancer
Institute.
Review articles