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Physarum Polycephalum (Sequential DNA Replication/Cell Cycle) GERARD PIERRON*T, DAVID S

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Physarum Polycephalum (Sequential DNA Replication/Cell Cycle) GERARD PIERRON*T, DAVID S Proc. Nadl. Acad. Sci. USA Vol. 81, pp. 6393-6397, October 1984 Cell Biology Invariant temporal order of replication of the four actin gene loci during the naturally synchronous mitotic cycles of Physarum polycephalum (sequential DNA replication/cell cycle) GERARD PIERRON*t, DAVID S. DURICA*, AND HELMUT W. SAUER* *Department of Biology and Institute of Developmental Biology and tDepartment of Medical Biochemistry, Texas A&M University, College Station, TX 77843 Communicated by David M. Prescott, June 25, 1984 ABSTRACT The chronological sequence of replication for licated DNA in early S phase (10, 15), prompted us to deter- the four unlinked actin gene loci of Physarum has been estab- mine the chronology of replication of the four actin loci. lished. Southern hybridization analysis of density-labeled, In this communication we demonstrate that three of the bromodeoxyuridine-substituted DNA isolated from defined four actin loci are replicated at the time when only 5-10% of periods of S phase demonstrates that three actin loci (ard, the genome has replicated. The synchrony of DNA replica- ardC, ardO) are duplicated laVy, corresponding to the first tion at the gene level is such that two allelic DNA sequences 10% of the genome. The fourth locus (ard4) replicates later, of one actin locus are coordinately replicated. The fourth ac- between 80 and 100 min into S phase and after 75% of DNA tin locus is replicated when DNA synthesis is 75% complet- synthesis is completed. Gene-dosage determinations, based on ed. Moreover, this temporal order of replication remains in- the quantitation of hybridization signals from DNAs isolated variant, when monitored either through two consecutive S from various tinmes during S phase, confirm the results ob- phases in a single macroplasmodium or over a period of at tained with bromodeoxyuridine-substituted DNA and increase least 400 generation times in suspension culture. The signifi- the temporal resolution. The chronological order ofreplication cance of this fixed order of replication is discussed in light of in the macroplasmodium appears constant through two con- the replication-transcription-coupling hypothesis. secutive cell cycles and after prolonged growth in suspension culture. The precise chronology of DNA synthesis at the gene MATERIALS AND METHODS extends to the coordinate replication of allele pairs. level Cultures. The strain Tu 291, provided by F. Haugli (Trom- so University, Norway), was used throughput this investiga- It has been clearly demonstrated, both by cytological meth- tion. Obtained by crossing stains RSD4 by'RSD8 amoebae, it ods and density-labeling, that certain segments -of the eu- is 'a diploid derivative of the Wis 1 natural isolate (19). The karyotic genome replicate at defined time intervals in S synchronous cultures (macroplasmodia) were made accord- phase of the cell cycle (1, 2) in lower eukaryotes like Phy- ing to published procedures on Whatman filter paper no. 4. sarum (3) as well as in human cells (4). Heterochromatin is (20). Surface cultures (6-7 cm in diameter) were harvested generally, found to replicate late in S phase (5-7), whereas after mitosis II or III (MII or MIII).' certain potentially active genes (8, 9) replicate early. Em- DNA Extraction. About 108 nuclei were isolated from a ploying electron microscopic spreads of chromatin, we have macroplasmodium according to ref. 21 and immediately re- recently visualized actively transcribing genes in early-repli- suspended in 50 mM Tris HC1, pH'8.0/50 mM NaCl/10 mM cated DNA ofPhysarum. Typically, both coding strands of a EDTA. DNA was extracted and purified as described (22). newly replicated locus are transcribed in early S phase (10). As monitored by gel electrophoresis, the DNA was consis- A relationship between the onset of DNA replication in S tently 50 kilobases (kb) or greater in size. phase and transcription has been documented for yeast (11), BrdUrd Incorporation. Surface cultures were treated at 10 Drosophila qmbryos (17), and tissue culture cells (13, 14) as min before mitosis (prophase) until harvested in S phase. well for Physarum (15), although the significance of this Drug concentrations in normal growth medium (20) were correlation is not understood. A detailed analysis of the tem- 100, 5, and 100 pg/ml for BrdUrd, fluorodeoxyuridine, and poral 'squence of pIplication and expression of defined uridine, respectively (3). Under these conditions, at least genes should further our understanding of the mechanisms two mitotic cycles take place on 15 ml of medium. underlying cell proliferatiop and cell differentiation (16). Isolation of BrdUrd-Substituted DNA. After a BrdUrd Physarufn; is aptly shited for such an analysis, due to the pulse, the DNA was isolated and purified on CsCl gradients. unparalleled mitotic synchrony of a macroplasmodium, in To' recover the newly replicated heavy-light (HL) DNA from which 108 nuclei divide and initiate DNA replication within unreplicated adjacent 'spquences, we digested the isolated <5 mim every 10 hr.i DNA with HindIII. Typically 100-150 ,g of DNA was di- Taking advantage of restriction fragment length polymor- gested overnight in 100-150 units of the enzyme. An aliquot phisms and Physarum's amenability for genetic analysis, it is of 10-20 yg of restricted DNA was removed for Southern possible to analyze the Mendelian segregation of specific hybridizations (23) and the rest of the restricted DNA sam- multigene family members, as was recently done for the ac- ples was diluted to 9 ml in 50 mM TrisHCl, pH 8.0/50 mM tin genes ofPhysarum (17). This knowledge about the segre- NaCl/10 mM EDTA/0.1% Sarkosyl. After addition of 11 g gation pattern'of the actin gene family (17), coupled with the of'solid CsCl, the restricted DNA was centrifuged for 60-72 natural synchrony of the nuclear replication cycle of Phy- hr at 36,000 rpm in a Beckman 50 Ti rotor. Pooled fractions sarum (16, 18), the evidence for the temporal order of DNA synthesis (3), and tfhe preferential transcription of newly rep- Abbreviations: kb, kilobase(s); HL, heavy-light; LL, light-light; MII and MIII, second and third mitoses. The publication costs of this article were defrayed in part by page charge tPresent address: Laboratoire de Microscopie Electronique, Institut payment. This article must therefore be hereby marked "advertisement" de Recherches Scientifiques sur le Cancer, Centre National de la in accordance with 18 U.S.C. §1734 solely to indicate this fact. Recherche Scientifique, 94802 VilleJuif Cedex, France. 6393 6394 Cell Biology: Pierron et aL Proc. NatL Acad Sci. USA 81 (1984) of light-light (LL) and HL DNA were dialyzed against 10 bridization bands are very similar in molecular weight to the mM Tris HCl, pH 8.0/1 mM EDTA and precipitated with HindIII restriction fragments of the parental strain Wis 1, ethanol. detected with yeast and Drosophila probes (17). By compar- Hybridization Analysis. Restricted DNA was analyzed by ing the pattern of alleles for the actin gene family of Phy- the protocol of Southern (23) under standard conditions (0.45 sarum we conclude that strain Tu 291 is homozygous for M NaCl/0.045 M sodium citrate, pH 7, 680C) for 20 hr in the three ofthe four ard (actin restriction-defined fragments, ref. presence of 10% dextran sulfate. The actin gene probe was a 17 and Table 1): ardA (allele A2, 17.4 kb and 7.2 kb), ardB 3.6-kb HindIII fragment isolated by gel electrophoresis and (allele B,, 13.6 kb), and ardD (allele Di, 4.5 kb) and hetero- electroelution (24) from plasmid pSpGl7 (25). It contains the zygous for ardC (allele C,, 5.6 kb, and C2, 5 kb). complete coding sequence of a sea urchin cytoskeletal actin The genotype of strain Tu 291 allows us to assay the order gene (25, 26). The fragment was labeled by nick-translation of replication of the four actin linkage groups as well as the (27) to a specific activity of 5-20 x 107 cpm/pg of DNA. replication of one pair of actin alleles. For convenience, we Autoradiographs were scanned in a Beckman DU8 spectro- have labeled the restriction bands (in order of decreasing photometer equipped with a gel scan compu-set, Main pa- size): A17, B, A7, C1, C2, and D, where the letter designates rameters were 500 nm; slit, 0.2 nm; gel slit, 0.05 mm; gel and the locus, numbers 1 and 2 designate the alleles, and num- chart speed, 0.4 cm/min; integration of selected areas with- bers 17 and 7 designate the two fragments derived from the out background subtraction. single complex locus (Table 1 and Figs. 2-4). Separation of Early- and Late-Replicated Nuclear DNA RESULTS Fractions. To probe for the sequence of actin gene replica- tion, we first increased the resolution of preparative separa- Analysis of the Actin Gene Loci of Physarum Strain Tu 291. tion of unifiliary BrdUrd-substituted HL from nonreplicated By hybridization of nick-translated yeast and Drosophila ac- LL fractions of the nuclear DNA. tin probes to restricted DNA from the diploid strain Wis 1, Partially BrdUrd-substituted DNA was obtained from cul- and its haploid progeny, four unlinked actin loci have been tures treated from 10 min before telophase until distinct time detected in Physarum (17). For each of three of these loci, points in S phase (see Materials and Methods). Labeling pe- two alleles were defined as single HindIII (or single EcoRI) riods were based on our knowledge of the kinetics of DNA restriction fragments of different length. The fourth locus is replication (30), the lack of G1 phase (3, 18), and the high complex because two HindIII (or three EcoRI) restriction degree of mitotic synchrony in Physarum. Purified DNA fragments cosegregate upon meiotic assortment.
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