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Identification of New Genes Required for the Maintenance of Chromosome Integrity in Drosophila Melanogaster

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Identification of New Genes Required for the Maintenance of Chromosome Integrity in Drosophila Melanogaster Turkish Journal of Biology Turk J Biol (2014) 38: 880-897 http://journals.tubitak.gov.tr/biology/ © TÜBİTAK Research Article doi:10.3906/biy-1404-1 Identification of new genes required for the maintenance of chromosome integrity in Drosophila melanogaster 1 1 2, Francesca CEPRANI , Franco SPIRITO , Roberto PIERGENTILI * 1 Department of Biology and Biotechnologies, Sapienza University of Rome, Rome, Italy 2 Institute of Biology, Molecular Medicine, and Nanobiotechnologies at the National Research Council (CNR), Sapienza University of Rome, Rome, Italy Received: 01.04.2014 Accepted: 21.07.2014 Published Online: 24.11.2014 Printed: 22.12.2014 Abstract: Although genome-wide RNA interference (RNAi) screens for mitotic genes are not new in the literature, most of them lack the cytological characterization of the cell karyotype as for chromosome integrity. Here, the effects of RNAi on chromosome structure in S2 cultured cells of Drosophila melanogaster were analyzed. The cytological phenotype of 1132 genes selected by coexpression with known mitotic genes was scored. Cytological and statistical analysis of the treated cells allowed the identifying of 81 loci whose inactivation brings a level of chromosome breakage significantly higher than in the control. Many of the genes characterized in the present work had never been associated with a cellular function; in other cases, their putative role is apparently unrelated to the chromosome breakage phenotype. These results suggest novel biological roles for the proteins encoded by the identified genes and indicate that the number of loci required for chromosome integrity is much larger than expected. Moreover, these results strongly suggest that the compilation of a list of coexpressed genes for any given function would result in a largely incomplete set of data, and that quite surprisingly a more complete collection of loci may be obtained using screening criteria different from selection. Key words: Cancer, functional coexpression, genome instability, karyotype, S2 cultured cells, segmental aneuploidy, RNAi 1. Introduction – evolved very early and was already present in the first, RNA-interference (RNAi) is experimentally used for gene primitive eukaryotes; as a result, organisms not showing silencing via a double-stranded RNA (dsRNA) targeting a RNAi probably lost it during evolution (Cerutti and Casas- complementary messenger RNA (mRNA) and promoting Mollano, 2006). The use of RNAi has been largely and its degradation by a nuclease-dependent cut. Although successfully used for the analysis of single gene silencing this acronym was first used by Fire et al. (1998) in studying as well as for the screening of genome-wide collections the model organism Caenorhabditis elegans, this biological of genes, showing that the resulting phenotype is usually phenomenon had already been observed before, though highly specific and penetrant (Mohr et al., 2010). This not completely understood, in several organisms such as approach allowed achieving extremely important results, transgenic plants (Ecker and Davis, 1986; Napoli et al., especially in the investigation of basic cell life phenomena 1990), Neurospora crassa (Romano and Macino, 1992), such as metabolism, mitosis and cytokinesis, chromosome Caenorhabditis elegans (Guo and Kemphues, 1995), structure and behavior, and mitotic spindle functions. and Drosophila melanogaster (Pal-Bhadra et al., 1997), Remarkably, in most screenings RNAi is not used to indicating that RNAi is widely present in most eukaryotes. identify genes required to maintain mitotic chromosome Notably, some eukaryotes lack all or most of the RNAi integrity, principally because this type of analysis cannot machinery; among others, these include some protozoa be automated (Conrad and Gerlich, 2010). Thus, genome- (Robinson and Beverley, 2003; DaRocha et al., 2004), and wide screenings for this phenotype are largely missing several fungi including Saccharomyces cerevisiae (Aravind from the scientific literature. et al., 2000; Nakayashiki et al., 2006; Drinnenberg et al., The DNA of living cells is subject to many types of 2009). Some researchers suggest that this mechanism – molecular lesions, including base modifications, single- probably a defense against exogenous, potentially harmful and double-strand breaks, and intra- and interstrand cross- dsRNA such as that of viruses or transposable elements links between bases. Double-stranded DNA breaks (DSBs) * Correspondence: [email protected] 880 CEPRANI et al. / Turk J Biol are probably the most deleterious lesions, as they can with polyploidy than aneuploidy; although chromosome result in chromosome aberrations (CAs), cell death, and number abnormalities are frequently associated with the neoplastic transformation (Khanna and Jackson, 2001; van neoplastic transformation (Torres et al., 2008; Williams Gent et al., 2001; Mills et al., 2003). To counteract the effects and Amon, 2009), aneuploidy is a potential tool to target of DSBs, living organisms have evolved 2 main mechanisms cancer cells, since even transformed cells are sensitive to for repairing their DNA: homologous recombination (HR) genomic unbalances (Bannon and Mc Gee, 2009; Williams (San Filippo et al., 2008) and nonhomologous end joining and Amon, 2009). As a general mechanism, aneuploidy – (NHEJ) (Lieber, 2010). In the HR pathway the broken ends including segmental aneuploidy – leads to alterations of undergo a recombinational process with the undamaged the gene copy number, and these alterations may influence sequence of either the sister chromatid or the homologous not only the gene itself (and/or the protein it encodes) chromosome, which is used as a template for accurate DSB but also its molecular or functional interactors (Torres repairs. In the NHEJ pathway, after a limited degradation et al., 2008; Veitia et al., 2008; Henrichsen et al., 2009), (Huertas, 2010), broken ends are ligated irrespective of which leads to the potential deregulation of tens of genes. homology, thus resulting in a small sequence deletion at In this perspective, it becomes crucial to identify those the joining site. The latter mechanism is intrinsically error- genes that determine the genome stability by controlling prone, and in addition to the aforesaid deletion it may also the chromosome integrity, since the effects of even a lead to various types of chromosomal rearrangements, single un- or misrepaired DNA break may have harmful such as transpositions and reciprocal translocations consequences. Of great help is the fact that these genes are (Lieber et al., 2006; Weinstock et al., 2006). Experimental widely conserved in most eukaryotes, so it is conceivable analyses using ionizing radiation and restriction enzymes that studying them in a model system, such as cultured have shown that DSBs are the principal lesions leading Drosophila S2 cells interfered with by RNAi, might provide to the formation of CAs (Natarajan and Obe, 1978; Obe important suggestions about the role of their human et al., 1992; Vamvakas et al., 1997; Richardson and Jasin, orthologs, with the advantage that in Drosophila the 2000; Obe et al., 2002; Tsai and Lieber, 2010). Interestingly, interference is easily achieved and the karyotype is simpler after a first burst, a second round of radiation-derived CAs than in humans due to a reduced chromosome number. may appear several cell generations after the first genomic In 2008 Somma et al. identified a number of genes insult, indicating that its effects on genome stability might having a role in mitosis. To achieve this result, they created become evident even after a long time (Streffer, 2010). a list of genes coexpressed with other, known mitotic genes. Because of the lack of homology, the erroneous ligation In order to evaluate the coexpression, they used the Pearson of 2 centromere-containing broken DNA ends by NHEJ correlation coefficient and, since this variable goes between leads to the formation of a dicentric chromosome able to –1.00 and + 1.00 and its highest values express increasing start the break-fusion-bridge cycle (McClintock, 1951), levels of positive correlation, they focused on the range which in turn makes CAs more complex. CAs were of [0.85, 1.00]. Specifically, Somma et al. evaluated the associated with neoplastic transformation in man a long frequency of contemporary expression of a reference gene time ago (Nowell and Hungerford, 1960; Levan, 1967; (first variable) against any other gene (second variable) of Rowley, 1973; Zech et al., 1976; Fukuhara et al., 1979; the D. melanogaster genome using microarray data from Hatano et al., 1981; Tsujimoto et al., 1984; Finger et al., 89 different experiments. They repeated this analysis 6 1986; Rabbitts et al., 1988; Le Beau et al., 1993), frequently times, using 6 reference genes connected to mitosis, and because of up-, down- or misregulation of genes important created a merged table of coexpression using the average for DNA replication, DNA repair, checkpoint control, value of each gene against the 6 reference genes. Finally, and mature ribonucleoprotein (mRNP) biogenesis they analyzed the first approximately 1000 genes that had (Aguilera and Gomez-Gonzalez, 2008; Clémenson and a Pearson correlation coefficient in the above mentioned Marsolier-Kergoat, 2009; Kerzendorfer and O’Driscoll, range. The screening was performed by studying the 2009; Mitelman et al., 2010). Acentric fragments, lacking cytological phenotype of cultured S2 cells after RNAi a centromeric region, are not able to
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