Counteracting spontaneous transformation via overexpression of rate-limiting DNA base excision repair enzymes
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Carcinogenesis, Vol. 22, No. 9,
1335-1341, September 2001
© 2001
Oxford University Press
COMMENTARY |
Counteracting spontaneous transformation via overexpression of rate-limiting DNA base excision repair enzymes
DNA Repair Unit, Mutagenesis Laboratory, Istituto Nazionale Ricerca Cancro, Largo Rosanna Benzi no. 10, 16132 Genova, Italy
Correspondence: Email: gfrosina@hp380.ist.unige.it
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Abstract |
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DNA damage of endogenous origin may
significantly contribute to human cancer. A
major pathway involved in DNA repair of endogenous
damage is DNA base excision repair (BER). BER is
rather efficient in human cells but a
certain amount of endogenous damage inevitably
escapes mending and likely contributes to human
carcinogenesis. Apart from some glycosylases
that are particularly sluggish (e.g. 8-oxoG
DNA glycosylase), recent work suggests that the
general rate-limiting steps of BER may be
trimming of 2-deoxyribose 5-phosphate in
case the process is started by a monofunctional
glycosylase or trimming of a 3'-blocking
fragment, in case BER is started by a
bifunctional glycosylase or in the case of
single-strand breaks produced by free
radical attack.
Overexpression of the
5'-deoxyribophosphodiesterase (dRPase) domain of DNA
polymerase ß, on the one hand, and of yeast
APN1 protein, containing an efficient 3'
repair activity, on the other, may lead to improved
BER in mammals. The recently characterized S3
protein of Drosophila, containing
both dRPase and 3'-trimming activities, could also
be considered for overexpression studies. The
possible protecting role of enhanced BER
could be investigated in cultured rodent
embryonic fibroblasts undergoing spontaneous
transformation, a most interesting system
that merits rediscovery.
Abbreviations: AP, abasic; BER, base excision repair; dRP, 2-deoxyribose 5-phosphate; dRPase, 5'-deoxyribophosphodiesterase; MEF, mouse embryonic fibroblast; MMS, methylmethanesulfonate; 8-oxoG, 8-oxo-7,8-dihydroguanine; PCNA, proliferating cell nuclear antigen; PNK, polynucleotide kinase; pol ß, DNA polymerase ß; ROI, reactive oxygen intermediate.
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Introduction |
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Most human
cancers may be considered `spontaneous' in nature
as no evident specific inducing agent is usually
identified. Development of cancer is linked
to a number of genetic alterations caused by
both endogenous and exogenous factors (1).
These alterations are continuously selected
for improved proliferation according to a
Darwinian process. This phenomenon is fortunately very
long and development of frank malignancies may
take decades. The very slow selection of the
spontaneous cancer phenotype has always been
a major hindrance to cancer research. The development
of new strategies to counteract the phenomenon
may take advantage of simpler and more
convenient systems that mimic the in vivo
process.
Most primary animal cells exhibit a limited lifespan in culture and eventually undergo senescence, during which time the cells cease to proliferate with resultant cell death (2). With varying frequency, especially dependent on the species of origin, a few cells survive the senescence crisis and acquire unlimited proliferative potential. At the same time, measurable in months, they also spontaneously become neoplastic, displaying an increasing capacity to grow in soft agar and induce tumors in nude mice. A number of comprehensive reviews on in vitro spontaneous transformation have been produced (3–8) and for a detailed description of the phenomenon we refer to them. Transformation of cultured rodent fibroblasts has been used until recently to assess the carcinogenic properties of various drugs and metabolites (9,10), but exploitation of this phenomenon to investigate new strategies to prevent or reverse the spontaneous cancer phenotype has declined. This is somewhat surprising given the important achievements that have been made in understanding the molecular changes that underlie spontaneous in vitro transformation and the parallels between this phenomenon and human carcinogenesis. We here propose making use of spontaneous in vitro transformation to investigate the possible protecting role of accelerated DNA base excision repair (BER), the main pathway that repairs endogenous damage in mammalian cells.
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Spontaneous transformation in rodent and human cells |
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 TopAbstractIntroduction Spontaneous
transformation in... How
similar are spontaneous...Stimulating
DNA repair of...Rate-limiting
steps of BERPossible
ways to stimulate...Concluding
remarksReferences |
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When embryonic cells are taken from a mouse and placed
in culture they usually divide a limited
number of times (10–15 population doublings
or 15–20 days), after which most cells die (3,11,12).
Some cells survive this crisis and become
immortal, i.e. capable of indefinite growth.
Cells that survive the crisis and become
immortal are relatively frequent in rodent cell
cultures, with an immortalization rate of
1–10x10–6per
cell per generation (13,14).
Variants that survive the crisis display
aneuploidy, chromosomal aberrations and mutations in a
number of tumor suppressor genes (15–18),
thus indicating significant genotypic
alterations, but still have very limited proliferation
capacity and no ability to grow in soft agar or
induce tumors in nude mice (19).
Within a period measurable in months cells
slowly acquire improved proliferation potential and a
number of characteristics that are typical
of neoplastic cells, i.e. increased colony
forming ability, loss of contact inhibition,
elevated saturation density and ability to grow in soft
agar and to induce tumors in nude mice (3,4,6,8).
The process clearly involves continuous
selection. Spontaneous immortalization and
transformation is more frequent in mice than in rats
but can be considered a general feature of
rodent cells (6).
Unlike rodents, spontaneous in vitro transformation of human or avian cells is a very rare event (20). Three cases of spontaneous transformation of human fibroblasts have been reported (21–23), together with a few other cases with other cell types, such as epidermal keratinocytes (24) and mammary epithelial cells (25). Genuine derivation of transformed cells from normal diploid parent cells has even been questioned in some of the above cases (5). Spontaneous immortalization is more frequent in normal cells from patients with Li–Fraumeni syndrome who carry inherited mutations of the p53 gene (26–28). It is clear that the combination of events that lead human fibroblasts to spontaneously immortalize and subsequently transform in culture is extremely rare in comparison with rodent cells. A possible explanation for this is that the number of mutational events required to confer immortality on human cells is higher than the number required for rodent cells (7,29–31). For example, human fibroblasts control the number of cell divisions by telomere shortening, a mechanism that is not present in mice (32,33). Further, rates of spontaneous mutation are lower in humans (34). This may be linked to their higher repair capacity [demonstrated for nucleotide excision repair but probably applying to repair of endogenous damage as well] and slower metabolism (35–37). As a consequence, no human cell can acquire a sufficient number of alterations necessary for indefinite growth before the onset of crisis.
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How similar are spontaneous transformation of cultured rodent cells and human carcinogenesis? |
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Spontaneous in vitro
transformation of rodent cells resembles
human carcinogenesis in some aspects. First, like most
human cancers it occurs in the absence of
any intentional or known treatment. Second,
a major agent responsible for spontaneous
malignant transformation of mouse embryonic fibroblasts
(MEFs) is atmospheric oxygen (38).
Lowering the concentration of oxygen from 18
to ~1% markedly reduces the phenomenon (38).
Addition of catalase to the culture medium
decreases the incidence of chromosomal
aberrations and delays or prevents the onset of
neoplastic transformation of mouse fibroblasts,
thus indicating that H2O2
and/or the derivative •OH are factors
involved (39). The
proliferative effect of superoxide radicals varies
with the stage of neoplastic progression (40).
Some indications point to a role of oxygen
in human cancer too. More than 20 years ago
it was observed in pioneering epidemiological studies
that there is little contribution of
industrialization and general pollution to
the spontaneous rate of occurrence of cancer and
that oxygen metabolism may play a role (41,42).
Much subsequent evidence has confirmed this
notion and has pointed to endogenous damage
as a factor in the etiology of cancer, with particular
reference to products of oxygen metabolism
(reviewed in refs 43–46). A small but
probably steady production of carcinogenic
radicals is the price to be paid for aerobic
metabolism. Third, the spontaneous
transformation of MEFs is accompanied by inactivation
of tumor suppressor genes with frequencies and
characteristics similar to those found in
human tumors. For example, mutations in the
tumor suppressor genes p53 and INK4a are
common, albeit not sufficient, events in the
spontaneous immortalization/transformation
of normal fibroblasts (15–17,47–48)
and these are precisely the two most
frequently inactivated tumor suppressor
genes in human cancer, irrespective of tumor type, site
and patient age (49,50).
Fourth, cultured murine fibroblasts steadily
increase their proliferation capacity, reminiscent of
tumor progression (51).
The process of spontaneous neoplastic progression
in vitro has been described in detail by
Kraemer et al. (19)
and Cram et al. (52).
The process can be divided into four stages
that correlate with a steady progression in karyotypic
instability, including aneuploidy and
chromosomal aberrations of marker chromosomes,
as occurs in most malignancies. Further, most
other indicators of in vitro
progression, such as saturation density, a criss-cross
and piled up growth pattern,
anchorage-independent growth (19),
inability to undergo apoptosis (53),
alterations in extracellular matrix
components (54) and amplification
potential (55), correlate
with tumorigenicity, i.e. the better cells grow in the
Petri dish, the better they also grow in
vivo producing tumors in nude mice.
Fifth, transformed MEFs and tumors (e.g.
3-methylcholantrene-induced mouse sarcomas)
can share common antigens against which lymphoid
cells mediate both primary and secondary immune
reactions (56) and
immunization with transformed MEFs may in some cases
protect mice from subsequent challenge with
live tumor cells (57).
There are also important specific features that differentiate spontaneous neoplastic transformation in vitro from human tumorigenesis.
Many factors that influence tumorigenesis, such as tissue architecture, blood and lymphatic circulation, cell–cell interactions and a myriad of components (e.g. hormonal) present in the in vivo extracellular milieu, are lost in the Petri dish.
It has been established that cell density influences the rate of spontaneous transformation, i.e. cells transform faster if cultured at high density. An epigenetic origin for this phenomenon has been proposed as an adaptive response of cells to conditions of moderate growth constraint rather than selection among genetically altered cells (58,59), although this view has been challenged (60).
Senescence in cultured mouse cells is not linked to telomere shortening and telomerase activation is not required for transformation, in contrast to what occurs in human tumors (32,33).
In planning transfection experiments a further drawback of MEFs is that these slowly growing primary cells may have low transfection frequencies and the occurrence of crisis may hamper the recovery of a sufficient number of clones.
The above specificities of MEFs undoubtedly represent serious problems in extrapolation of results to the in vivo process of carcinogenesis when factors that prevent or correct the neoplastic phenotype are investigated. Yet, some biases (e.g. those linked to cell density) may be significantly attenuated with appropriate controls. Care should be taken to use MEFs from mouse outbred strains (e.g. CD-1) with no tumor virus (e.g. MuMTV) infection in order to minimize possible influences of inbreeding and virus particles (4). Finally, reagent kits that allow efficient transfection of MEFs have been developed and are commercially available (48).
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Stimulating DNA repair of endogenous damage to delay the onset of spontaneous transformation |
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An increased efficiency of protective
mechanisms may delay the threshold
accumulation of cancerous events beyond the average
human lifespan. A significant portion of
carcinogenic hits in humans is probably of
endogenous origin (reviewed in refs 43–46).
Endogenous damage is rather frequent and characterized
by elevated miscoding properties. For
instance, according to recent estimates
~1000 8-oxo-7,8-dihydroguanines (8-oxoG), ~400 uracils
and ~9000 abasic (AP) sites are generated
daily per human cell (T. Lindahl, quoted in
ref. 61). An important repair
mechanism dealing with endogenous lesions is
BER (62). Development of mouse
knockout strains is currently pursued in
order to define the role of BER in vivo.
Deletion of BER activities leads to various phenotypic
consequences, ranging from arrest of embryonic
development [such as in the cases of mice
deficient in the major AP endonuclease
APE/HAP1 (63), DNA polymerase ß (pol
ß) (64) or XRCC1 protein
(65)] to mild [strains deficient in
3-alkyl-N-purine glycosylase (66,67),
poly(ADP) ribose polymerase (68),
8-oxoG DNA glycosylase (OGG1) (69)
or uracil-DNA glycosylase (UNG) (70)]
or minimal [strains deficient in the endonuclease III
homolog NTH1 (71)] effects,
thus raising new questions as to the
significance and back-up supply of different BER
activities. Despite the complexity of this
emerging picture, it is most likely that
endogenous lesions escaping the `cleaning' activity
of BER may contribute to spontaneous
mutagenesis/carcinogenesis (43–46,61).
In particular, some lesions with elevated
miscoding properties (8-oxoG and
4,6-diamino-5-formamidopyrimidine) are
repaired with low efficiency in human cells (72,73).
Recently, achievements have been made in
defining the enzymatic reactions that limit
the velocity of the whole process. We wonder whether
the ability of mammalian cells to repair
endogenous lesions may be increased by
overexpression of one or more rate-limiting
BER activities and whether this may influence the rate
of spontaneous transformation of MEFs.
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Rate-limiting steps of BER |
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BER is a three-armed pathway,
depending on the kind of endogenous lesion
involved (reviewed in ref.74; Figure
1
).
Some lesions (e.g. uracil) are removed by
monofunctional glycosylases (UNG in this
case) that only detach the altered base with no
incision of the resultant AP site (Figure 1,
left pathway). Other lesions (e.g. thymine
glycol) are removed by bifunctional DNA glycosylases
(NTH1) that, in addition to base removal, also
incise the resulting AP site by an
associated AP lyase activity (Figure 1,
right pathway). The right-hand pathway is
also the main route by which single-strand
breaks generated by reactive oxygen intermediates
(ROIs) are sealed, a reaction that requires prior
removal of a 3'-blocking fragment by a
3'-phosphatase/phosphodiesterase activity (75).
Finally, in the case of BER initiated by monofunctional
glycosylases (left-hand pathway), resynthesis of
a number of repair patches 2–10 nt long is
required, dependant on proliferating cell
nuclear antigen (PCNA), a phenomenon that
occurs in competition with the predominant DNA pol
ß-dependent 1 nt insertion pathway (76–78;
Figure 1,
bottom left pathway).
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are involved in the long patch pathway. The
2–10 nt long damaged DNA fragment is displaced
during polymerization and removed by DNase IV
(FEN1). DNA ligase I is the main sealing
activity in the long patch pathway. In the case
of bifunctional glycosylases (right-hand
pathway) the AP site generated by the
glycosylase activity is further 3' incised by
an associated AP lyase. The 3' blocking
fragment left by AP lyases is trimmed in human
cells by the 3' phosphodiesterase activity
associated with APE/HAP1 or by the PNK–XRCC1
complex. Synthesis is performed via pol
ß only and ligation proceeds as for the short
patch pathway initiated by monofunctional
glycosylases. The S3 ribosomal protein of
Drosophila can remove either a dRP group or
a 3'-blocking fragment.
Recent work has investigated the
rate-limiting steps of BER (reviewed in ref.74).
The efficiency of the glycolytic (base
removal) step may be important in this regard and
depends on the lesion involved. For example,
repair of 8-oxoG in mammalian cells is
inefficient in comparison with that of other endogenous
lesions (72,73)
and this is most probably linked to the poor
catalytic properties of OGG1 (79,80).
Once the base has been removed, BER likely
slows down in subsequent trimming steps. It
has been shown by Srivastava and co-workers (81)
that when BER is initiated by a
monofunctional glycosylase (UNG) the rate-determining
step is removal of 2-deoxyribose 5-phosphate (dRP)
by APE/HAP1 incision (81,82).
dRP is predominantly removed in mammalian
cells by the 5'-deoxyribophosphodiesterase (dRPase)
activity associated with DNA pol ß (8 kDa
domain) (83). When BER is
initiated by a bifunctional glycosylase (right-hand
pathway in Figure 1
)
or when a single-strand break is induced by ROIs
the rate-limiting step is most likely removal of
3'-blocking deoxyribose fragments (74,75).
3'-Deoxyribose fragments are predominantly
removed in mammalian cells by the 3' repair diesterase
activity associated with APE/HAP1 (75,84).
The latter protein probably evolved to act
preferentially on natural AP sites rather
than deoxyribose fragments located at DNA strand breaks
(85) and the efficiency
of its diesterase activity is low, being
~200-fold lower than the hydrolytic activity (84).
A second protein also removes 3'-blocking
fragments in eukaryotic cells. The recently
characterized human polynucleotide kinase (PNK)
is endowed with a phosphatase activity
potentially capable of restoring
conventional 3'-OH termini to DNA single-strand breaks.
This activity is stimulated by XRCC1 protein (86).
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Possible ways to stimulate the BER pathways |
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Removal of dRP, the rate-limiting
step of BER initiated by monofunctional DNA
glycosylases (left-hand branch in Figure 1),
might be accelerated by overexpression of
the 8 kDa domain of DNA pol ß (74,82).
It has been demonstrated that this domain retains its
dRPase functionality when isolated from the rest
of the protein (83). The
isolated domain efficiently removes 5'-dRP from a
pre-incised AP site and its catalytic mechanism
as well as a detailed functional analysis of
its protein sequence have been determined (87,88).
It has recently been shown that expression
of the 8 kDa domain effectively protects pol
ß-deficient cells from methymethanesulfonate
(MMS)-induced cytotoxicity (82).
In contrast, expressing the isolated pol ß DNA
synthesis activity (Flag-K35A,K68A,K72A pol ß
fragment; 82) has no protecting effect and
may in fact lead to a genome instability
phenotype as overexpression of polymerase results
in increased spontaneous mutagenesis and a highly
mutagenic tolerance phenotype towards DNA
damaging drugs (89,90).
The rate of the
right-hand branch of BER in Figure 1
(initiated by a bifunctional DNA glycosylase)
may be increased by overexpression of the
major yeast AP endonuclease APN1. Tomicic et al.
(91) have shown that
Chinese hamster cells become more resistant
to DNA damaging agents such as MMS and H2O2
after transfection of the yeast but not the
human AP endonuclease gene. Increased
resistance to the genotoxicity of oxidizing and
alkylating agents after overexpression of
APN1 has also been reported by the group of
Mark Kelley (92; personal communication). In contrast,
expression of human APE/HAP1 has no
protective effect in human cells with
respect to ROI-generating agents (93,94).
These results indicate that expression of
yeast (APN1) but not human (APE/HAP1) AP
endonuclease protects mammalian cells from certain
oxidative and alkylating agents. The
different results obtained with the yeast
and human enzymes can probably be explained by their
different substrate features. As mentioned
above, APE/HAP1 shows a very weak 3' repair
diesterase activity and probably evolved to incise
natural AP sites rather than remove 3'-fragments
generated by bifunctional glycosylases or
free radical attack (85). The yeast
APN1 gene encodes an AP endonuclease
function that is homologous to
Escherichia coli endonuclease IV and, like the
bacterial enzyme, is associated with a
robust diesterase activity. The capacity to
trim 3'-deoxyribose fragments may thus represent
an important protecting factor. The recently
discovered 3'-phosphatase activity
associated with human PNK might also be investigated
for the possibility that its overexpression may
stimulate repair of lesions removed by
bifunctional glycosylases or ROI-generated
single-strand breaks (86).
Finally, the Drosophila ribosomal protein S3 has been reported to be endowed with the capacity to remove both a dRP group from DNA substrates containing 5' incised AP sites and obstructive 3' lesions from DNA substrates containing 3'-incised sites (95). Overexpression of this protein in mammalian cells may thus accelerate both pathways of BER. Further, S3 protein can perform cleavage of 8-oxoG residues, another inefficient step of human BER (96,73). Thus, S3 is a multifunctional repair protein that may act specifically at points of slow-down. Combined overexpression of two proteins (e.g. the 8 kDa pol ß domain with yeast APN1) might be devised in order to achieve acceleration of both pathways of BER (74,97).
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Concluding remarks |
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By definition, any factor with
possible cancer preventing activity has to
be investigated in normal cells, in order to determine
its protecting efficacy and possible undesirable
toxic effects. Normal cells from Li–Fraumeni
patients are currently employed to
investigate various chemopreventive and antitelomerase
agents (28,98,99).
While these cells are of the utmost interest, being
of human origin and characterized by spontaneous
reproducible transformation, they present
the drawback of inherent p53 pathology.
Rodent fibroblasts in culture may represent an
alternative and versatile system for the
preliminary evaluation of protective
factors. The latter might be investigated on a clonal
population that spontaneously evolves from a
normal genotypic/phenotypic situation to a
malignant one. Thus, the system could be useful
to investigators of cancer avoidance mechanisms
other than DNA repair. For example, a
protective factor that deserves increasing
attention is caloric restriction. A number of studies
have shown that caloric restriction can
modulate endogenous damage and substantially
reduce the rate of spontaneous
mutagenesis/carcinogenesis (100,101),
a phenomenon observable in yeast as in man (102).
The underlying mechanisms are currently being
investigated in vivo (103),
but could also be conveniently studied in the MEF
system.
Agents with possible therapeutic properties might also be tested on transformed fibroblasts reverting to a more `normal' phenotype. For example, expression of one or more tumor suppressors can reverse the neoplastic phenotype (104,105), among which p53 is the most promising (106). Super-trans mutants retaining normal transactivating capacity in the presence of dominant negative mutant p53, which inhibits the wild-type protein, have recently been isolated (107). Their tumor suppressing capacity could preliminarily be investigated in the MEF system. Further, it has recently been shown that p53 interacts with and stabilizes DNA pol ß on the damaged substrate, thus markedly improving the efficiency of BER in vitro (108–110). Hence, p53 overexpression might have beneficial effects on repair efficiency as well.
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Acknowledgments |
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I thank my colleagues Massimo
Bogliolo, Enrico Cappelli and Ottavio Rossi
who are trying to translate into facts the theories
expressed in this paper. The generous
collaboration of Dr Mark R.Kelley (Indiana
University, IN) and Dr Robert W.Sobol (NIEHS,
Research Triangle Park, NC) is gratefully
acknowledged. This work was partially
supported by the Italian Association for
Cancer Research (AIRC), Telethon, Italy, the National
Research Council (grant no. 99.02487.CT04)
and the Italian Ministry of Health.
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[Abstract/Full Text]
Received February 19, 2001; revised March 29, 2001; accepted April 11, 2001.
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