on radiation genetics xi11 international congress genetics...symposium on radiation genetics : xi11...

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 tolerance repair. The UV protective capacity and light-inducible RNA photoreactivation 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 characteristics 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

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 organisms 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.

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 mediated 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 complicated 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.

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 mechanism 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 sensitivity 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 tolerance gene. In Table 1, I have classified the tlr-j's as tolerance genes with the allowance of '/2

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 -

* 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

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, dependent 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\‘-endonuclease 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-


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 mutation 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 phenomenon: 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 depends 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-

156 S. KONDO

revertants of E. coli mutants ezrA- (BRIDGES et al. 1973) and lex- (MOUNT, personal 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 replicative 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 spontaneous mutation (KIMURA and OHTA 1973) proposed to account for the evolution of various proteins (DAYHOFF 1972).

EVOLUTION OF DNA REPAIR

Let us assume that the main energy source for the origin of primitive, replicative 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 ancestor 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 important 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


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 living 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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