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Saccharomyces Cerevisiae MOLECULAR AND CELLULAR BIOLOGY, Nov. 1992, p. 5249-5259 Vol. 12, No. 11 0270-7306/92/115249-11$02.00/0 Copyright © 1992, American Society for Microbiology Identification of a New Set of Cell Cycle-Regulatory Genes That Regulate S-Phase Transcription of Histone Genes in Saccharomyces cerevisiae HAIXIN XU, UNG-JIN KIM, TILLMAN SCHUSTER, AND MICHAEL GRUNSTEIN* Molecular Biology Institute and Department ofBiology, University of California, Los Angeles, California 90024-1570 Received 20 April 1992/Returned for modification 9 June 1992/Accepted 11 August 1992 Histone mRNA synthesis is tightly regulated to S phase of the yeast Saccharomyces cerevisiae cell cycle as a result of transcriptional and posttranscriptional controls. Moreover, histone gene transcription decreases rapidly if DNA replication is inhibited by hydroxyurea or if cells are arrested in G1 by the mating pheromone a-factor. To identify the transcriptional controls responsible for cycle-specific histone mRNA synthesis, we have developed a selection for mutations which disrupt this process. Using this approach, we have isolated five mutants (hpcl, hpc2, hpc3, hpc4, and hpc5) in which cell cycle regulation of histone gene transcription is altered. All of these mutations are recessive and belong to separate complementation groups. Of these, only one (hpcl) falls in one of the three complementation groups identified previously by other means (M. A. Osley and D. Lycan, Mol. Cell. Biol. 7:4204-4210, 1987), indicating that at least seven different genes are involved in the cell cycle-specific regulation of histone gene transcription. hpc4 is unique in that derepression occurs only in the presence of hydroxyurea but not a-factor, suggesting that at least one of the regulatory factors is specific to histone gene transcription after DNA replication is blocked. One of the hpc mutations (hpc2) suppresses 8 insertion mutations in the HIS4 and LYS2 loci. This effect allowed the cloning and sequence analysis of HPC2, which encodes a 67.5-kDa, highly charged basic protein. Histone mRNAs are synthesized and accumulated prefer- transcribed divergently from common regulatory elements entially in S phase of the eukaryotic cell cycle, partly as a (19, 49). cis-acting regulatory elements, including three result of transcriptional controls which cause the rate of upstream activator sequence (UAS) repeats and a negative synthesis of histone mRNAs to increase during S phase. repressor element, have been identified in the region be- Also, posttranscriptional regulation results in the preferen- tween the HTAI and HTB1 genes (34). The UAS elements tial degradation of histone mRNAs outside of S (reviewed in are required for cell cycle-dependent activation of the HTAl- reference 17). These two mechanisms of regulation function HTB1 pair, while the negative element is necessary for to decrease mammalian histone mRNA levels after DNA repressing the transcription of this gene pair during stages synthesis is blocked in the presence of hydroxyurea (HU) other than S phase. Deletion of the negative element has (17). In this report, we focus on cell cycle-specific, transcrip- resulted in the constitutive transcription of histone mRNAs tional control of histone mRNA synthesis. during the yeast cell cycle (29, 34); however, histone mRNA The human histone H4 gene is transcribed more efficiently accumulation is still S phase specific in these cells as a result (3- to 10-fold) in S-phase extracts than in extracts taken from of posttranscriptional degradation of histone mRNAs in cells at other stages of the cell cycle (18). Mammalian stages other than S phase (34, 54). upstream promoter elements responsible for this regulation As an initial step toward unraveling the mechanism of cell have been identified (1, 6, 16, 28, 42). Moreover, fusion of cycle-dependent histone gene transcription, three genes the 5' end of the mouse histone H3 gene to the bacterial (HIR1, HIR2, and HIR3) encoding factors that regulate neomycin resistance (neo) gene causes the bacterial mRNA histone mRNA synthesis have been identified (35, 44). to be in a cell manner (3). cis- synthesized cycle-specific Mutations in these genes were detected by including in a acting regulatory sequences and their trans-acting protein yeast strain an integrated HTA1 promoter-lacZ fusion gene factors are likely responsible for regulating histone mRNA synthesis (7, 10, 11, 14, 50; reviewed in reference 33); and screening for mutants which overexpressed 1-galactosi- however, the molecular details of the regulatory mechanism dase. These mutants, which also lost normal periodic tran- scription of HTA1 mRNA, did so as a result of a disruption by which this occurs are still under investigation. in function through the repressor element (35). While these The yeast Saccharomyces cerevisiae provides a system which allows the identification genetically of trans-acting mutants altered the degree of repression of several other factors that regulate cycle-specific histone mRNA synthesis. histone gene loci upon treatment of the cells with HU, other Yeast histone genes are organized into four genetically cell cycle-regulated genes such as the HO endonuclease (31), unlinked gene pairs: two copies each for the histone H2A- involved in switching of mating loci, and CDC9 (36), the H2B gene pair (HTA1-HTB1 and HTA2-HTB2) (20, 51) and structural gene for DNA ligase, were expressed normally. two copies for the histone H3-H4 gene pair (HHT1-HHFI Interestingly, these hir mutations all suppress a well- and HHT2-HHF2) (48). Each of the histone gene pairs is characterized yeast mutant in which a solo 8 element, serving as the promoter of a yeast transposon (Ty), has been inserted at HIS4 and LYS2 loci his4-9128 and lys2-1288 (44). 8 insertions at these two loci have previously been shown to * Corresponding author. alter either transcriptional initiation (his4-9128) or termina- 5249 5250 XU ET AL. MOL. CELL. BIOL. tion (lys2-1288), producing a His- or Lys- phenotype (9, 47, TABLE 1. Yeast strains 52). It is noteworthy that among the many loci which have been identified as SPT (suppressor of Ty), two of them, sptll Strain Relevant genotype Source and sptl2, have been characterized as mutations at the YM259 AMTa ade2 his3 tyrl ura3 L. Johnson promoter region of the HTAI-HTBI locus. The wild-type YM214 MA4Ta ade2 his3 iys2 ura3 L. Johnson HTAI-HTBI gene pair on a high-copy-number plasmid can UKY9 MATa ade2 his3 tyrl ura3 hpcl This study also suppress his4-9128 and lys2-1288 (8). Furthermore, HXY100 AMTa ade2 his3 tyrl ura3 hpc2 This study recessive mutations in three known SPT genes (SPT1, HXY1O1 MATTa ade2 his3 lys2 ura3 hpc2 This study UKY24-1 MATa ade2 his3 Iys2 ura3 hpc3 This study SPTIO, and SPT21) have also been found to derepress UKY24-2 MATa ade2 his3 tyrl ura3 hpc3 This study HTAI-HTB1 transcription upon the inhibition of DNA syn- UKY35 MATa ade2 his3 tyrl ura3 hpc4 This study thesis. SPT1 has been shown to be allelic to HIR2, while UKY35-25 MATa ade2 his3 lys2 ura3 hpc4 This study SPTIO and SPT21 are distinct from other histone-regulatory UKY36 AlATa ade2 his3 tyrl ura3 hpcS This study genes (44). Therefore, it seems that S. cerevisiae employs a UKY36-5D MATa ade2 his3 Iys2 ura3 hpcS This study complex system that involves two types of cis-regulatory HXY103 MATa ade2 hpc2 ura3 HIS3 LYS2 This study elements and many trans-acting factors to coordinate his- HXY104 MATa ade2 hpc2 ura3 HIS3 LYS2 This study tone synthesis with the cell division cycle. HXY116 MATa ade2 lys2 HPC2/HPC2::URA3 This study To isolate new regulatory mutants that alter periodic 21-1A MATa his3 his7 leu2 trpl ura3 hirl M. A. Osley 24-SB MATa his7 leu2 trpl ura3 hir2 M. A. Osley transcription of the yeast histone genes, we used a direct 30-9C MATa ade2 leu2 trpl ura3 hir3 M. A. Osley selection. This was done by fusing the HTAI promoter to the FW1237 MATa ura3 his4-9128 lys2-1288 F. Winston bacterial neo gene, which when transcribed at high levels FW1238 MATa ura3 his4-9128 lys2-1288 F. Winston causes yeast cells to become resistant to the neomycin analog G418. It is expected that mutations in the trans-acting factors repressing the HTAI promoter should result in con- stitutive high levels of neo synthesis. This analysis identified and then digested by SaII to create sticky ends. The recir- five mutations (hpcl, hpc2, hpc3, hpc4, and hpcS [hpc for cularized plasmids were screened by sequencing, and two histone promoter control]), each in a different complemen- deletions that removed HTA1 coding sequences up to 29 and tation group. Four of these mutations belong to different 18 bp upstream of the ATG codon were picked to make the complementation groups from those isolated previously as following two constructs. The XhoI-SaiI fragment from each histone-regulatory mutations (35). In addition, hpc2 shows a of these two plasmids containing the HTA1-HTBI promoter very strong Spt- phenotype, suppressing both his4-9128 and region was subcloned into the SalI site of pSEYC58 plasmid lys2-1288 insertion mutations. This feature was used to clone (13) in such an orientation that the Sall site close to the the HPC2 gene. This gene encodes a 624-amino-acid, highly EcoRI site is conserved and the direction ofHTAI transcrip- charged basic protein which can fully complement the Spt- tion is opposite that of the lacZ gene contained in pSEYC58. phenotype and restores normal cell cycle control of histone These constructs, after partial digestion with BamHI, were HTAJ gene expression in an hpc2 strain. digested with Sal, and the large fragments were ligated to the 922-bp BgiII-SalI fragment of the neo gene from the MATERIALS AND METHODS bacterial transposon TnS (23). Colonies were screened on LB plates containing 10 ,ug of neomycin per ml after trans- Media, chemicals, and strain constructions.
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