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Symposium on Radiation Genetics : XI11 International Congress of
Genetics
RADIATION GENETICS I N MICROORGANISMS AND EVOLUTIONARY
CONSIDERATIONS1
SOHEI KONDO
Department of Fundamental Radiology, Faculty of Medicine, Osaka
University, Kita-ku, Osaka, Japan 530
ABSTRACT
Recent knowledge of UV-resis tance mechanisms in microorganisms
is re- viewed in perspective, with emphasis on E . coli.
Dark-repair genes are classified into “excision” and “tolerance”
(ability to produce a normal copy of DNA from damaged DNA). The
phenotype of DNA repair is rather common among the microorganisms
compared, and yet their molecular mechanisms are not universal. In
contrast, DNA photoreactivation is the simplest and the most
general among these three repair systems. It is proposed that DNA
repair mechanisms evolved in the order: photoreactivation, excision
repair, and toler- ance repair. The UV protective capacity and
light-inducible RNA photoreacti- vation possessed by some plant
viruses are interpreted to be the result of solar UV selection
during a rather recent era of evolution.
HE high sensitivity of the living organism to radiation is a
fundamental Tphenomenon and is due to the interaction of high
penetrating energy with the genetic material indispensable and
unique to living things. The number of DNA lesions required for
inactivation of a genome, either by X or UV, increases with
increase in genome complexity (TERZI 1961 ; KONDO 1964). This
progressive radioresistance is believed to be mostly ascribable to
DNA repair (HOWARD- FLANDERS 1968). Our knowledge of the biological
effects of radiation at the molecular level has recently increased
considerably ( SETLOW and SETLOW 1972) and yet irradiation of a
living thing with ionizing radiation often still present more
questions than it answers. This is partly due to the complexity of
the DNA damage induced (TOWN, SMITH and KAPLAN 1973). In contrast,
the major cause of UV effects is known to be pyrimidine dimers.
Therefore, the complexity of UV genetics in microorganisms must be
mostly ascribed to the complex genetic apparatus. All living things
are now believed, on the basis of ample evidence, to be descendants
of a common ancestor (DAYHOFF 1972). Therefore, I believe thct
radiation genetics in microorganisms is worthwhile reviewing from
the evolutionary standpoint in order to make a framework into which
diverse charac- teristics may be put together (KONDO 1972; RADMAN,
ROMMELACRE and ERRERA 1973).
Supported by grants from the Ministry of Education, Japan and
the Toray Science Foundation. Abbreuiations: X (X or y rays); UV
(ultraviolet); PR (photoreactivation); Exc (Excision); Inc
(Incision); Rec (recombinational[al]); TDHT
(5-thyminyl-5,6-dihydrothumine); dimers (cyclobutane-type
pyrimidine d i m e r s in DNA); Pol (DNA polymerase [activity]);
Exo (DNA exonuclease [activity]); superscripts “S”, “R’, “-”, e.g.,
U V S or UVB (UV-sensitive or -resistant for plaque- or
colony-forming ability) ; Exc- (excisionless).
Genetics 78: 1W-161 September, 1974
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150 S. KONDO
RADIORESISTANCE MECHANISMS
Radioresistance mechanisms of some representative
microorganisms, with emphasis on Escherichia coli, will be
discussed in the sequence of radiobiological processes:
PHYSICO-CHEMICAL BIOCHEMICAL BIOLOGICAL ) ( STAGE I->( STAGE
)+( STAGE Excision Repair Repair
Protection Reuersal or Tolerance
PROTECTION
Bacillus megaterium or subtilis in a spore phase is several
times more radio- resistant than in the vegetative phase, but the
resistance may simply reflect the spore-specific conformation of
DNA evolutionarily selected to provide a dormant state of genetic
information.
The RNA’s of plant viruses are protected to various extents
against UV by protein coats (see review KLECZKOWSKI 1971) : TMV
(tobacco mosaic virus)- RNA becomes 20- or 30-fold more UVR with
the protein coat of strain U (1 ) or U(2) than the naked RNA, and
the protein coat of potato virus X gives about 2.5-fold protection;
but the coats of tobacco necrosis virus provides no protection.
This variation suggests that these viruses and the protective
capacity of their protein coats have evolved rather recently.
PHOTOREACTIVATION
The most efficient repair we know of today is PR of UV damage to
DNA: a photochemical reversal of dimers to monomers via
DNA-photoreactivating enzyme bound to dimers (SETLOW 1966; HARM,
RUPERT and HARM 1971). The gene phr of E. coli is a structural gene
for the DNA-PR enzyme since h phage carrying this phr gene produces
a high yield of PR enzyme in the infected host SUTHERLAND, COURT
and CHAMBERLIN 1972). DNA-PR enzyme is a constitu- tive enzyme, for
the enzyme activity increases in yeast with increases in the number
of the phr genes per cell from one to four (RESNICK and SETLOW
197213) and it also exists in cultured cells of higher forms (COOK
1970). The total number of PR enzyme molecules per E. coli cell is
only about 20 (HARM, RUPERT and HARM 1971).
The following evidence supports the hypothesis that the phr gene
originated as an advantageous gene at a very early date when there
was greater danger from solar UV. The PR enzyme in E. coli is
located near the chromosome (MURAOKA and KONDO 1969). As so far
tested, this enzyme is ineffective for photorepairing damage other
than dimer except for the thymine-cytosine adduct (IKENAGA, PATRICK
and JAGGER 1971). PR action spectra among various orga- nisms are
very similar (JAGGER, TAKEBE and SNOW 1970) and exceptional cases
may be explained by the evolution of the phr gene or by the loss of
the gene through a random drift after the solar UV threat
disappeared.
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RADIATION GENETICS IN MICROORGANISMS 151
RNA PR is very different from DNA PR. DNA-PR enzyme does not
bind to UV-irradiated RNA (RUPERT 1961). PR of UV-irradiated
TMV-RNA is medi- ated by what appears to be a new PR enzyme (HURTER
et al. 1974). This RNA- PR “enzyme” is inducible by visible light
in tobacco leaves (MURPHY and GORDON 1971). Apparently RNA-PR
“enzyme” is the product of a more compli- cated gene system than
the gene phr for DNA-PR enzyme, an indication that DNA-PR enzyme
evolved earlier than RNA-PR “enzyme”.
EXCISION REPAIR
The isolation of strain polAi (DE LUCIA and CAIRNS 1969; GROSS
and GROSS 1969) was a milestone. The “patch and cut” model (Figure
IA) is now more favored than the “cut and patch” (Figure IB).
Transforming activity of UV- inactivated B. subtilis DNA is partly
restored after incubation with M . luteus UV-endonuclease, E. coli
DNA polymerase I and DNA ligase (HEIJNEKER et al. 1971). X-rayed
DNA is also repaired by a similar in vitro repair system without
the endonuclease or by lysates of wild-type B. subtilis cells but
not by lysates of pol- cells -(LAIPIS and GANESAN 1972). That pol-
strains of E. coli were
EXCISION REPAIR &
A ) PATCH AND -c-- -- ENDONUCLEASE CUT
BI CUT AND PATCH
C) LONG PATCH
DJ R E P L I C A T I V E R E P A i h
POLYMERASE I LIGASE
1 =+....- - - - 3
- -b -b
EXONUCLEASE POLYMERASE Ill‘ LIGASE
- - I - . . ‘. :. : .. . .- -‘. , .. , - . : *- . * . :.:-
++
EXTENSIVE DEGUDATION AND POLY~ERIZATION
+ -4- POLYMERASE 111’ ~OLYUERIZATION AND SEALING - - L
E ) COPY CHOICE P E P A I R - 3 ASYKHETRIC DNA REPLICATION
SISTER-STRAND EXCHANGE I
TOLERANCE REPAIR
FI RECOMBINATIONAL R E P A I R ---&+ - -? GAP FILLING
WITH
SISTER-STRAND 6 ----;i DIUER GAP IN DAUGHTER P REPAIR SYNTHESIS
SISTER-STRAND CROSS-OVER - G J 3 E NOVO S Y N T H E S I S
R E P A I R STRAND w DE NOVO SYNIHESIS
FIGURE 1.-Some models of DNA dark-repair. A) From KELLY et al.
1969. B) From KUSH- NER et al. 1971; TAKETO, YASUDA and SEKIGUCHI,
1972. C) From COOPER and J~ANAWALT, 1972. D) This emerges from
SHAMAZU, MORIMYO and SUZUKU, 1971; MASKER, HANAWALT and SHIZUYA,
1973; YOUNGS and SMITH 1973a. The Pol 111’ stands for Pol 111, or
Pol I1 M induced Pol without 5’ - 3’ Exo. E) From VAN SLUE 1972. F)
From RUPP and HOWARD-FLANDERS 1968. G) From LEHMANN 1972.
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152 S. KONDO
found among mutants selected primarily for the XE and UVs
properties (OGAWA 1970; KATO and KONDO 1970) also supports the
model of polymerase-I-dependent repair synthesis.
TOLERANCE REPAIR
Inc- (uurA- or uvrB-) strains of E. coli are inactivated at the
rate of about 100 dimers per genome per lethal hit. This means that
the cell has a tolerant mecha- nism capable of producing a
damage-free copy of DNA from damaged DNA. A tolerance-less mutant
can be inferred from a synergistic increase in its UV sensi- tivity
with combination of an inc gene. The target theory applicable fo r
such classification is given below.
Target theory for DNA repair: We define the tolerance capacity
of a cell, A, as the number of unrepaired dimers per genome per
lethal hit. Under conditions where interference between excision
and tollerance repairs is negligible (e.g., cultures synchronized
in the Go or G, phase), we can express the survival [SI versus dose
[D (erg/mm2)] relationship in terms of A and r [fraction of dimers
repaired Ly excision repair] as follows (KONDO et al. 1970; KONDO
1972):
S = 1 - (1 - ekD)"; k = 6 (1 - r ) / A , (1) where 6 stands for
the initial number of induced dimers per genome per ergmm-2.
Combine an established Inc- strain inc-i- (with reduced repair Ti)
to the assumed tolerance defective tZr-j- (with reduced tolerance A
, ) under test. Then, if the excision repair has no interaction
with the tolerance, we have
6 ( 1 - r ) / A = k : wildtype 6 ( l - r i ) / A = k j :
mutantinc-i- 6 (1 - r ) / A , = k , : mutant tZr-j- 6 (1 - Ti) / A
f = kii : double mutant inc-i- tZr-j-
If the ratio f, defined as ( k J k ) / ( k i j / k i ) , is
unity, gene t h j is an exc-repair-independent toler- ance gene. In
Table 1, I have classified the tlr-j's as tolerance genes with the
allowance of '/2
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RADIATION GENETICS IN MICROORGANISMS
TABLE 1
Classification of UV-sensitive genes*
153
Organism Excision-repair genes Tolerance-repair genes
E . coli uurA, uurB, [uurC] recA, [ zab] , lex(exrA) [ras],
polA(resA) recB, r e d , recF [polC], mutU, [uurD] [ r e d ]
S. cereuisiae radl, rad2 xsl (rad52) uxsl (radlb)
Coliphage T4 u x, y , 1206 H . inflzunme [uur l ] , uur2
recl
Minimum tolerance capacity reported
1.3 dimers/genome: strain uvrA- recA-
-6 dimers/genome: haploid strain radl-18 uxsl
-4 dimers/genome: T4vy 1-2 dimers/genome: strain uur2- r e d
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* Genes in brackets are tentatively classified from indirect
evidence. Original references are as follows: (uurA-, recA-) :
HOWARD-FLANDERS and BOYCE (1966). (uurA-, reCB-): HOWARD- FLANDERS
et d. 1971. (mb-, recA-) : CASTELLAZZI, GEORGE and BUTFIN (1972). (
l e z uvrA-) : MOUNT and KOSEL (1973). (uurB-, r e d - ) and ( r e
d - , reCB-): HORII and CLARK (1973). ( r e d - , r e d - ) : KATO
(1972). (polA-, exrA-): YOUNGS and SMITH (197313). (po2A; poZCt8) :
YOUNGS and SMITH (1973a). (ras): WALKER (1969). (mutU-, recA-):
SIEGEL (1973). (uurD-, uurA-): OGAWA, SHIMADA and TOMIZAWA (1968).
(rad2,xsl): NAKAI and MATSUMOTO (1967). (radl-18 u z s l ) : KHAN,
BRENDEL and HAYNES (1970); BRENDEL and HAYNES (1973). ( u , x ) ,
(u,y) and (U, 1206) : SYMONDS, HEINDL and WHITE (1973). (uur2;
recl-) : LE CLERC and SETLOW (1973).
end uur2-recl- (LECLERC and SETLOW 1973) are almost completely
toleranceless (Table 1 ) . The tolerance of E. coli partly depends
also on the genes Zex (MOUNT and KOSEL 1973), zab (CASTELLAZZI,
GEORGE and BUTTIN 1972), recB(C), recF and recL (HORII and CLARK
1973). Genes lex, zab and recA are involved in control of cell
septation. The tolerancelessness and other pleiotropic radiosensi-
tiveness of the recA- strain are explained as the results of
post-UV reckless division (Figure 2). In contrast, a
rec-repair-proficient strain inc- shows a pro- nounced delay in
post-UV division (Figure 2) supposed to be necessary for the slow
gap filling. Similarly, an extremely XsUVs strain of slime mold
amoebae has been recently identified as of rackless division type
(DEERING and JENSEN 1973). All these mutants seem primarily
concerned with repair coordination (see below).
COORDINATION A N D M U L T I P L E P A T H W A Y S
We have presumably too many radiosensitive genes for excision
and tolerance repairs-already more than 20 loci in E. coli (TAYLOR
and TROTTER 1972) and 33 genes in S. cereuisiae (MORTIMER and
HAWTHORNE 1973; and MORTIMER, personal communication). Since E.
coli (yeast) cannot have more repair than the two (three) kinds, as
argued before, we must look for roles other than as repair enzymes
for the majority of them. Three alleles, poZAl in P3478 (-1% Pol;
5’+ 3’ Exo+), its derivative JG112 (-0.1% Pol; 5’+ 3’ Exof) and
resAl (< 0.1 % Pol; 5’ + 3’ Exo+ ) , have the same UV
sensitivity despite the differential abnormality of polymerase and
dimer excision, and are only twice as UVs as
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154 S. KOlVDO
E’ICURI: 2-Differrntial lethal modes of E. coli K12 strains; u d
d (possessing wildtpye DNA rrpair), uvrA- (incisionless), r e d -
antl uvrA-recA- (S. KO” ancl H. ~ C I I I K A W A - R Y O . unpub-
lished).
Ovrrnight rulturrs wrre clilutrd ahout 100 times and exposrcl to
U\’ at doses (rrg ‘him?) of 100, 40, 44). and 2. mprctivrly (at
about 1 % survivnls, except for the uurA-recA- which was at about 0
. 1 %). for wild. umA-. rmA- and rmA-utvA- strains. Irracliiitwl
cells wcTc iricuhated at 37” on thin nutrient agar layers and
photographed after 5 hr incubation. Wild: W36W; uurA-: NI?-9 (a
drrivative of 11’362.3); recA-uvrA-: n cleriratire of N17-9
contnining il recA- allrle transclucrd from N23-53 (See OGAWA,
SSIIMADA and TOMI~AWA 1968); rmA-: AB2463 (HO\\..ARD-FIANDERS and
TIIERIOT 1966). The rwA- strains NW-53 H. &AWA 1970), JC5088
(13’11,1~1:m ancl CI-ARK 1969) antl JC1569 (CLARK 1%7) also show4
reckless division piitterns siniilar to that of An2463.
allele poZA’ZO7 (Pol+; 5’ 4 3’ Exo-) (LEHMAN and CHIEX 1973 and
personal communication; KATO 1972; GLICKMAN et al. 1973a.b; KONDO
and RYO. un- published). From this. I assume a coordination system
such that the bacterium recognizes the abnormality of polymerase.
turns off the polymerase-I-dependent pathway. and stimulates a
backup repair system. The “long patch” repair, de- pendent on the
genes r.ecB(C) and/or recA and ATP and stimulated in strain polAI
(COOPER and HANAWAI.T 1972; KATO 1972). probably reflects the
assumed backup repair, for mutnnts pol-recB- and pol-recA- are not
Yiablc (MONK and KINROSS 1972). The low repair efficiency of the in
uitro excision repair system may be explained by the lack of
coordinators effective for the sequential action of repair
enzymes.
It is puzzling that no mutants defective in the structural gene
for U\‘-endo- nuclease have been identified except the gene U in T4
(SATO and SEKICUCHI 1972). Genes uvrA and urd3 could he
coordinators. If so, they may regulate activation of endonuclease
genes or their products so that strains uvrA- and uwB- are
incisionless. Then, organisms can have duplicated structural genes
of UV- endonuclease and somc! of the ramified ones could be
effective for other kinds of hast. damage. Micrococcus luteus has
two kinds of endonuclease: one nicks both X- and UV-irradiated DNA
and the other UV-irradiated DNA only (CARRIER and SETLOW 1973). All
the UV” strains of M. luteus have a normal endonuclease activity
(except a double mutant) whereas endonucleaseless mutants are UV“,
nearly normal or slo\v in incision. and slow in post-UV DNA
synthesis (OKUBO. NAKAYAMA and TAKAGI 1971; VAN Sr.wrs 1972). This
ma?; suggest double ex-
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RADIATION GENETICS IN MICROORGANISMS 155
cision-repair pathways: ( 1 ) cut and patch (or patch and cut)
and (2) replicative or copy-choice repair (Figure 1). A nick-primed
replicative repair synthesis (Figure 1D) is indicated by the
following cases. A temperature-sensitive muta- tion at a gene
linked closely to locus uurA mimics the mutation uvrA- at 42” but
at 30” provides the UV-irradiated cells with a high rate of
survival and a capacity to slowly incise dimer-bearing DNA with
little release of dimers to the acid- soluble fraction-a slow
patch-(SHIMAzu, MORIMYO and SUZUKI 1971). Yeast shows a bimodal
repair: what appears to be normal excision repair in the expon-
ential phase and a different type (“replicative” repair?) in the
stationary to early growth phase (REZNICK and SETLOW 1972a).
If an auxiliary repair operates concomitantly with excision or
tolerance repair, and if it is induced only after UV irradiation,
then it will not be easily detected. An inducible repair is,
however, easily demonstrated in the UV reactivation phe- nomenon:
survival and mutation of UV-irradiated phage increase after pre-
irradiation of the host o r introduction of UV-irradiated F’ into
the host (RADMAN, ROMMELAERE and ERRERA 1973; RADMAN 1974; GEORGE,
DEVORET and RADMAN 1973). This repair requires protein synthesis
(ONO and SHIMAZU 1966) and de- pends on genes recA (MIURA and
TOMIZAWA 1968) and lex (DEFAIS et aZ. 1971). It is not yet known
whether UV reactivation is induced by non-dimer type DNA damage as
is the case of UV-induced genetic recombination in phage (How-
ARD-FLANDERS and LIN 1973).
In addition to excision repair, B. subtilis has “spore repair”
which eliminates the spore photoproduct (TDHT) but does not
function for repair of dimers induced in the vegetative phase
(MUNAKATA and RUPERT 1972). TDHT is elim- inated (reversed to
monomers?) first by the spore repair and later repaired by the
excision repair which becomes active only at a later stage of
germination.
The assumed coordinated repair action by so many genes would
require a stage for its performance. I t may be served by the
cellular membrane or a similar structure, an explanation for
overlapping of some UVs mutations with membrane or division
mutations.
MUTAGENESIS
Viable offspring will be produced by irradiated organisms with
the help of DNA repair. If errors accompany the DNA repair, some of
them are expected to show up as induced mutations in the offspring.
From recent reviews (WITKIN 1969a; DRAKE 1970; AUERBACH and KILBEY
1971; DRAKE 1973; RADMAN 1973), I will quote briefly some essential
points.
One of the most important conclusions is that transformation of
a dimer into a mutation involves a complicated series of cellular
processes, probably through errors in some of the tolerance
repairs. The evidence is as follows: E . coli strains recA-, lex-
and recB- (re&-) are immutable, only slightly mutable and
weakly (WITKIN 1969b) or normally (HILL and NESTMANN 1973) mutable
by UV, re- spectively. whereas a Rec- strain recB- recC- sbcB-
recF- seems normally UV- mutable (KATO and CLARK, personal
communication). Mutants with reduced UV mutability have also been
reported with yeast (LEMONTT 1973): Pseudo-
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156 S. KONDO
revertants of E. coli mutants ezrA- (BRIDGES et al. 1973) and
lex- (MOUNT, per- sonal communication) possess a restored
radioresistance and yet remain hardly mutable by X and UV. The
presumed wild-type strain of H . influenzae is very resistant to
mutation by UV (J. K. SETLOW, personal communication). Proteus
mirabilis is immutable by UV, but its related species P. vulgaris
is UV-mutable (H. BOHME, personal communication). Obviously, UV
mutability is genetically controlled. Thus, a naive statement that
“primitive organisms evolved rapidly due to mutations induced by
the higher intensity of ancient solar UV” is not warranted.
It should be noted that excision repair is virtually
error-proof. I t is important to note that spontaneous mutability
is affected little by the
majority of radiosensitive genes [with some exceptions, e.g.,
uurE- (MATTERN 1971), mutU- (SIEGEL 1973) or pbeB- (HORIUCHI and
NAGATA 1973), and pol- (KONDO 1973) in E. coli and uxsl-l and xrsl-
l in yeast (VON BORSTEL, CAIN and STEINBERG 1971)] but greatly by
mutation of the structural gene for DNA repli- cative polymerase
(DRAKE 1973; HALL and BRAMMAR 1973). The replication- dependent
model of spontaneous mutagenesis is supported by various
observations (KONDO 1973), but is challenged by the time-dependent
model of neutral spon- taneous mutation (KIMURA and OHTA 1973)
proposed to account for the evolu- tion of various proteins
(DAYHOFF 1972).
EVOLUTION OF DNA REPAIR
Let us assume that the main energy source for the origin of
primitive, repli- cative DNA was the solar UV, which is supposed to
have been thousands of times more intense than today because of the
chemically reduced primitive atmosphere (SAGAN 1961, 1973). Then,
we expect that organisms which acquired UVR char- acters should
have had a great selective advantage to become the common ances-
tor of all present living things.
I assume that DNA-PR was the first repair acquired by our
ancestors, followed by excision and tolerance repairs. Since the
later repair factors were built into organisms when more species
were present, we expect them to have more diverg- ence due to the
high probability of independent origin. As discussed before, PR has
the highest generality among the three repairs. Excision repair is
also a very common phenomenon, found in T4 phage, Mycoplasma (SMITH
and HANAWALT 1969), bacteria, lower eukaryotes, higher forms, and
human cells, with the im- portant exception of cultured cells of
rodents; yet its molecular mechanism is not universal.
Chalamydomonas reinhardti ( SWINTON and HANAWALT 1973) lacks the
excision-repair mode of DNA repair despite its dark-repair ability.
It should be noted that excision repair is effective for various
kinds of chemical damage to purine or pyrimidine as well as
dimers.
Tolerance repair is expected to be more diverse than the above
two kinds of repair, for it repairs a wider range of DNA damage.
The repair systems acquired during evolution to deal with
spontaneous DNA damage (e.g., MOSES and RICH- ARDSON 1970) seem
incidentally capable of repairing X-ray damage and other damage.
Recombination, one of the largest contributors of tolerance genes,
is
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RADIATION GENETICS IN MICROORGANISMS 157
known to be phenotypically common but molecularly diverse among
living things.
An attractive hypothesis is that primitive organisms were
repeatedly created by solar UV and one of them was selected as the
common ancestor of present liv- ing organisms. It is tempting to
assume that this ancestral species was selected partly because of
its possession of the phr gene.
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