Origin recognition complex subunit 1
ORC1 accumulates transiently during a synchronous cycle that takes place in third larval instar eye imaginal disc cells (Asano, 1999). The onset of accumulation appears to result from transient activation of E2F-dependent transcription in the interval from late G1 to early S phase. Due to the methods of detection in these experiments, it was not possible to determine precisely when during the cycle ORC1 disappears. Confocal microscopy has been used to examine the timing of ORC1 disappearance with respect to two cell cycle markers: cyclin B (CycB), which accumulates from S phase until its destruction by the APC during mitosis, and the phospho-histone 3 (PH3) epitope, which marks M phase (Araki, 2003).
ORC1 is first detectable in the nuclei of cells that have not yet accumulated appreciable cytoplasmic CycB, consistent with the determination that ORC1 accumulates just before S phase entry. Examination of serial optical sections reveals that both proteins persist in cells as they transit G2. As the cells approach M phase, their nuclei rise apically and accumulate PH3 upon M phase entry. Remarkably, at this stage of the cell cycle, ORC1 is distributed in a 'donut' that surrounds the PH3, presumably because it has dissociated from the chromatin. Subsequently, both PH3 and ORC1 disappear as the cells complete mitosis and enter G1 of the following cycle (Araki, 2003).
The ability to monitor endogenous ORC1 in the experiments described above is limited by the level of antigen and the sensitivity of the antibody. In part to overcome these limitations and in part to monitor the regulation of various ORC1 derivatives, a transgene was generated that encodes a fusion of ORC1 to an epitope-tagged green fluorescent protein (GFP) derivative; the resulting fusion protein was expressed under control of the native orc1 promoter. Transgenic flies were generated by standard methods, and the distributions of endogenous ORC1 and transgenic ORC1-GFP were compared (Araki, 2003).
In general, the patterns of endogenous ORC1 and transgenic ORC1-GFP are indistinguishable in ovaries, embryos and the wing imaginal disc. In addition, detailed examination of the synchronous cell cycle transition in the eye disc reveals essentially identical behavior of ORC1 and ORC1-GFP: accumulation of ORC1-GFP prior to CycB in late G1 or early S phase, persistence of both ORC1-GFP and CycB throughout G2, removal of ORC1-GFP from chromatin during M phase upon accumulation of PH3, and disappearance of all three antigens (ORC1-GFP, CycB and PH3) upon entry into the subsequent G1. Thus, addition of the GFP-myc tag does not appear to perturb the cell cycle-modulated accumulation of ORC1 significantly (Araki, 2003).
It was of interest to determine whether ORC1 accumulation is regulated in a similar fashion in the asynchronously cycling cells that make up most of the imaginal discs. This seemed likely, given the appearance of ORC1 and ORC1-GFP 'donuts' in the asynchronous mitotic cells immediately anterior to the morphogenetic furrow. However, to survey the entire population of disc cells, use was made of fluorescence-activated cell sorting (FACS). In brief, imaginal discs from transgenic animals expressing ORC1-GFP under orc1 promoter control were collected, dissociated into individual cells, and sorted according to both DNA content and green fluorescence. The wing disc, which has been characterized in great detail by this method, and the eye antennal disc complex, were examined (Araki, 2003).
The cell cycle distribution of GFP-positive cells agrees with the analysis described above: ORC1-GFP is found predominantly in cells with S and G2 DNA content, consistent with the idea that it accumulates near the G1/S boundary, persists through G2, and disappears during M phase. During this stage of development, the eye and wing discs are governed by very different developmental programs; thus, the essentially identical regulation of ORC1 in these two tissues most probably reflects regulation by intrinsic cell cycle machinery rather than by developmental cues. In summary, the ORC1 in imaginal discs persists from late G1 into M phase when most of the protein is abruptly degraded before entry into the subsequent G1 (Araki, 2003).
One possible mechanism by which E2F transcription factor 2 (E2F2) could inhibit DNA replication is to act as a transcription factor to modulate the expression of at least one crucial replication factor. For example, if E2F2 was part of a repressor complex, loss of E2f2 function could lead to increases in replication gene expression that might trigger widespread DNA synthesis. In order to test this idea, an examination was made of the abundance of several mRNAs encoded by genes either known to be (e.g. Orc1, RNR2, PCNA) or possibly (e.g. Orc2 and Orc5) regulated by E2F. RNA was extracted from total follicle cell preparations and subjected to RT-PCR. Relative to rp49 controls, more Orc5 mRNA was reproducibly (n=4) detected in Df(2L)E2f2329/Df(2L)E2f2329 or Df(2L)E2f2329/E2f1-188 mutant samples, compared with wild type. An increased Orc2 mRNA level was also detected in some experiments (two out of four). For Orc1, RNR2 and PCNA there was no substantial difference in the amount of mRNA detected between wild type and E2f2 mutants. These data suggest (1) that E2F target genes are expressed at or above wild-type levels after loss of E2f2 function and (2) that de-repression of specific target genes, such as those encoding members of the ORC complex, could contribute to the inappropriate DNA synthesis seen in E2f2 mutant follicle cells (Cayirlioglu, 2001).
Proteins of the ORC complex assemble at origins of DNA replication and recruit factors (e.g. CDC45L) required to initiate bi-directional DNA synthesis. During oogenesis, localization of different ORC proteins within the follicle cell nuclei is dynamically regulated, coincident with changing patterns of DNA replication. ORC1, ORC2, ORC5, and CDC45L are distributed throughout the entire follicle cell nucleus when these cells are performing genomic replication during endocycle S phase, and after stage 10, these proteins are detected in foci that correlate with sites of chorion gene amplification. Because E2f2 mutant follicle cells fail to restrict DNA replication to gene amplification foci, the localization of replication factors was determined in follicle cells. Anti-ORC2, -ORC5 and CDC45L antibodies each label sites of chorion gene amplification in wild-type stage 10B egg chambers, presumably because these are the major sites of active DNA synthesis. This is consistent with the known role of these proteins in replication origin firing, and indeed female sterile mutants of Orc2 have reduced chorion gene amplification. In E2f2 mutant egg chambers, the distinct localization pattern of these replication proteins is lost, resulting in the detection of all three proteins throughout the entire nucleus. This phenotype is rescued by an E2f2 transgene. These data are consistent with the firing of origins in addition to those at the chorion loci causing inappropriate genomic DNA synthesis. Whether the mis-localization of ORC components and CDC45 in E2f2 mutants is a direct cause or a consequence of the ongoing ectopic replication is not known (Cayirlioglu, 2001).
The origin recognition complex (ORC) is an essential component of the prereplication complex (pre-RC) in mitotic cell cycles. The role of ORC as a foundation to assemble the pre-RC is conserved from yeast to human. Furthermore, in metazoans ORC plays a key role in determining the timing of replication initiation and origin usage. In this study a Drosophila orc1 allele was produced and analyzed to investigate the roles of ORC1 in three different modes of DNA replication during development. As expected, ORC1 is essential for mitotic replication and proliferation in brains and imaginal discs, as well as for gene amplification in ovarian follicle cells. Surprisingly, however, ORC1 is not required for endoreplication. Decreased cell number in orc1 mutant salivary glands is consistent with the idea that undetectable levels of maternal ORC1 during embryogenesis fail to support further proliferation. Nevertheless, these cells begin endoreplicating normally and reach a final ploidy of >1000C in the absence of zygotic synthesis of ORC1. The dispensability of ORC is further supported by an examination of other ORC members, whereas Double-parked protein/Cdt1 and minichromosome maintenance proteins are apparently essential for endoreplication, implying that some aspects of initiation are shared among the three modes of DNA replication. This study provides insight into the physiologic roles of ORC during metazoan development and proposes that DNA replication initiation is governed differently in mitotic and endocycles (Park, 2008).
This analysis of an orc1−/− mutant has revealed that endoreplication takes place in the orc1−/− SG cells throughout development as efficiently as it does in the orc1+/+ WT cells. DNA replication in orc1−/− cells occurs despite the absence of zygotic ORC1 expression, no detectable ORC1 in the SG cells either by immunostaining or Western blot analysis, and a lack of sufficient ORC1 function to support proliferation of the SG precursors before endoreplication starts (Park, 2008).
There are two possible interpretations of these results. The first is that an undetectable amount of remaining maternal ORC1 is enough to support the entire course of endocycles during embryonic and larval development. The second is that endoreplication does not require ORC. For the first interpretation to be the case, the undetectable residual maternal ORC1 must be able to support the 10-round endocycles to reach >1000C DNA content, even though it apparently is not enough to support proliferation in the same cells before endoreplication starts. Moreover, DNA synthesis during endocycles in the orc1−/− SG cells occurs as efficiently as in WT cells, with no indication of increased DSBs, suggesting that the number of firing origins is not reduced significantly during endoreplication, a sharp contrast to the inefficient DNA synthesis observed in many replication gene mutants. This interpretation would also require the cells to be in a state in which ORC1 is somehow immune to Anaphase Promoting Complex/Fizzy-related (APC/Fzr)-mediated degradation. The surge of APC/Fzr activity at the start of the endocycle stage in mid-embryogenesis and cyclic APC/Fzr activity at every round of endocycles would target any remaining maternal ORC1. The possibility cannot be ruled out that undetectably low levels of ORC remain associated with the chromosomal DNA throughout endocycles and are protected from the APC/Fzr by unknown mechanisms. However, this hypothetical pool of ORC would have to have special properties, capable of efficiently replicating 500 genome equivalents in the third instar SG cells but incapable of replicating the single genome in imaginal disc cells (Park, 2008).
Alternatively, ORC is in fact dispensable for endoreplication. If this is the case, whether or not ORC is required for the transition from mitotic to endoreplication remains to be determined and needs further investigation. In either case, how might DNA replication be initiated at each round of endocycles in the absence of ORC? The requirement of Dup/Cdt1 and MCM for endoreplication indicates that at least some components of the replication initiation cascade are shared between the 2 modes of replication (Park, 2008).
A simple model would be that there is an endoreplication-specific protein that brings in Dup/Cdt1 (and Cdc6 if it is required) to replication origins. One possibility is that there is an ORC1 homologue that is specific to endoreplication. In Arabidopsis there are two ORC1 proteins (ORC1a and ORC1b); one is specifically expressed during mitotic cycle and the other during the endocycle. ORC1a and ORC1b are highly homologous, and both associate with ORC2–6. However, in the case of Drosophila the entire ORC seems to be dispensable for endoreplication, which argues against this model (Park, 2008).
Another possibility is that there is a functional ORC homologue, protein X. It has been shown that Cdc6 can bypass ORC for replication initiation when tethered to an artificial origin on a plasmid DNA through a Gal4 binding site. Many Cdt1- and/or Cdc6-associated proteins reported in various organisms are candidates for protein X to bring Dup (and Cdc6) to origins and initiate endoreplication (Park, 2008).
It is also possible that ORC-independent endoreplication in flies involves an endoreplication-specific chromosomal structure. Structure-mediated replisome assembly occurs in bacteria when replication forks are frequently inactivated under normal growth conditions. It has been proposed that D-loops resulting from homologous recombination at DSBs mediate a DnaA-independent loading of DnaB onto arrested replication forks. Similar mechanisms that reactivate collapsed forks have been proposed in yeast and in telomeres where protein-mediated loop structures mimic the D-loop. Tightly controlled replication initiation by multiple layers of mechanisms (including regulation by ORC) and various checkpoint systems would preclude such DNA structure–dependent replisome formation during normal proliferation. However, it might be used in specialized replication, such as endoreplication, during which there is a physiologic increase of DSBs and checkpoint pathways are shut down. It would be of great interest in future to find the alternative mechanisms that regulate the ORC-independent initiation of DNA replication during endocycles (Park, 2008).
Drosophila melanogaster polytene chromosomes display specific banding pattern; the underlying genetic organization of this pattern has remained elusive for many years. This paper analyzed 32 cytology-mapped polytene chromosome interbands. Molecular locations of these interbands was estimated, their molecular and genetic organization was described and it was demonstrated that polytene chromosome interbands contain the 5' ends of housekeeping genes. As a rule, interbands display preferential 'head-to-head' orientation of genes. They are enriched for 'broad' class promoters characteristic of housekeeping genes and associate with open chromatin proteins and Origin Recognition Complex (ORC) components. In two regions, 10A and 100B, coding sequences of genes whose 5'-ends reside in interbands map to constantly loosely compacted, early-replicating, so-called 'grey' bands. Comparison of expression patterns of genes mapping to late-replicating dense bands vs genes whose promoter regions map to interbands shows that the former are generally tissue-specific, whereas the latter are represented by ubiquitously active genes. Analysis of RNA-seq data (modENCODE-FlyBase) indicates that transcripts from interband-mapping genes are present in most tissues and cell lines studied, across most developmental stages and upon various treatment conditions. A special algorithm was developed to computationally process protein localization data generated by the modENCODE project; it was shown that Drosophila genome has about 5700 sites that demonstrate all the features shared by the interbands cytologically mapped to date (Zhimulev, 2014. PubMed ID: 25072930).
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date revised: 10 October 2014
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