Unifying Homology Effects Carlo Cogoni

news & views Unifying homology effects Carlo Cogoni

University of Rome ‘La Sapienza’, Dipartimento di Biotecnologie Cellulari ed Ematologia, Viale Regina Elena, 324, 00161 Rome, Italy. e-mail: [email protected]

Meiotic silencing by unpaired DNA is a new mechanism, related to other homology-dependent gene silencing phenomena, with implications not only for genome protection against invasive nucleic acids but for genome maintenance and speciation as well.

The ability of DNA sequences to pair with A single ancient origin silencing). Based on these characteristics, each other on the basis of sequence homol- Neurospora crassa is haploid during vege- which differ from transvection as it is ogy is well recognized, being the basis for tative growth, whereas in the sexual cycle, observed in Drosophila, meiotic transvec- homologous chromosome pairing during two haploid nuclei of opposite mating tion has been renamed ‘meiotic silencing meiotic prophase. In the past decade, it has type fuse to produce a diploid cell, the by unpaired DNA’ (MSUD). Shiu et al.2 become clear that homology-based interac- zygote. The zygote immediately under- also discovered that MSUD is not tions between nucleic acids, both DNA and goes the two meiotic divisions, followed restricted to a few genes as was previously RNA, can be inﬂuential not only in accom- by one mitotic division, to produce hap- believed, but that virtually the entire plishing pairing and recombination during loid ascospores. Thus, the brief period genome is subject to this process. A note- meiosis, but also in regulation of gene after karyogamy and before meiosis is the worthy ﬁnding is that a putative RNA- expression at other times in the cell cycle. only time during which Neurospora is dependent RNA polymerase (RdRP) These regulatory mechanisms—collectively diploid. It has been known for some time encoded by sad-1 is necessary for MSUD. called ‘homology effects’1—constitute a that certain genes in Neurospora exhibit This suggests a common genetic basis for heterogeneous class of phenomena that are ‘meiotic transvection’3; in other words, meiotic silencing and previously charac- postulated to be mechanistically indepen- the two alleles need to be paired for proper terized post-transcriptional gene silencing dent processes. expression. In their study, Shiu et al.2 mechanisms induced either by transgenes Homology effects can be triggered by found that proper expression during or by double- stranded RNA, as these also the introduction of foreign nucleic acids, meiosis depends not only on the presence require RdRPs4–7. transgenes or double-stranded RNA mol- of paired alleles but also on the absence of ecules into cells, and result in a downregu- any unpaired allele. Apparently, Neu- Silencing the opposition

© http://genetics.nature.com Group 2002 Nature Publishing lation (silencing) of mRNA levels from the rospora can detect any DNA sequences Post-transcriptional gene silencing is a corresponding homologous endogenous unpaired during meiosis, and can silence mechanism by which supernumerary genes genes. In other cases, as in paramutation both unpaired DNA (self-silencing) and (multiple transgenic copies, for example) and transvection phenomena, interac- all homologous DNA present (trans- are detected and transgenic RNAs are con- tions between endogenous homologous alleles are required for gene silencing, or more generally, for proper regulation of gene expression. In a recent report in Cell, Patrick Shiu and colleagues2 describe a new mechanism of meiotic transvection occurring in the fungus Neurospora crassa. meiosis They ﬁnd that what has been called transvection unexpectedly shares features with other silencing phenomena, perhaps revealing a common ancestry. aRNA virus unpaired DNA RdRP Musical pairs. It has been proposed13 that repeti- (sad-1) tive DNA sequences could produce transcripts, often called aberrant RNAs (aRNAs), which might dsRNA differ in some way from normal mRNAs. These aRNAs are converted by RNA-dependent RNA poly- processing merases (RdRPs) into double-stranded RNA RdRP (dsRNA). Here, similar aRNAs are produced from (qde-1) unpaired DNA sequences during meiotic prophase. aRNA In Neurospora, two different RdRPs (qde-1 and sad- vegetative siRNA 1) are required for the two processes, suggesting growth that these two categories of aRNA may somehow differ from each other. Double-stranded RNA acti- vates a universally conserved silencing pathway (green arrows) that has evolved to counteract viral infections. Short interfering RNAs (siRNAs) derived homologous RNA from the processing of dsRNA can work as guides to degradation direct nuclease complexes to a target mRNA, lead- reptetive DNA ing to homologous RNA degradation. elements

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verted by RdRP to double-stranded RNA transcriptional gene silencing can be con- integrity, with broader biological implica- (dsRNA). This dsRNA is cleaved by a sidered a further exploitation of this mecha- tions than a mere defense strategy against ribonuclease III-like activity8 into small nism. Cells can somehow detect RNA parasitic DNA molecules. In haploid RNAs, also called short interfering RNA transcripts made from repetitive DNA organisms, rearrangements of the (siRNA)9, which, in turn, guide an RNA- sequences and use them as templates for genome, such as duplications and translo- degrading complex in the hydrolysis of RdRPs, producing dsRNA that can activate cations that occur during vegetative mRNA species homologous to the dsRNA homology-mediated RNA degradation (see growth, can disrupt intimate pairing of (see figure)10. One of the major biological figure). It is noteworthy that when a repeti- several genes, leading to gene silencing functions of post-transcriptional gene tive sequence is detected, all related and sterility during the sexual cycle. This silencing is to protect cells from invading sequences, even those scattered around the would prevent most genomic rearrange- nucleic acids11,12. The evolutionary origin genome, are inactivated in trans, preventing ments from being propagated. On the of this mechanism is probably related to the their expression and transposition. other hand, small changes in genome orga- development of the ability of a cell to recog- Whereas gene-silencing phenomena nization can escape MSUD and accumulate nize and deal with double-stranded RNA studied so far seem to be activated by DNA in the gene pool. Genome microhetero- molecules. The presence of large dsRNA segments present in supernumerary copies geneities, after accumulating in two geneti- molecules in a cell signals the existence of an or by the abnormal RNA transcripts, Shiu cally isolated populations, can be detected ongoing viral infection, because dsRNA is et al.2 describe a new silencing mechanism by MSUD during inter-population crosses, an intermediate produced during the life capable of examining the entire genome leading to infertility. Thus, MSUD could be cycle of many viruses. It is conceivable that during the first meiotic prophase, identify- a mechanism that promotes the reproduc- the first step was the evolution of enzymes ing DNA segments present in any odd tive isolation of species. The finding that capable of degrading dsRNA, and thus able number of copies or in the wrong chromo- mutations of sad-1 confer fertility on other- to directly counteract replicating viruses. somal location. As such, MSUD can be wise barren interspecific crosses within the A great increase in the efficiency of the seen as an additional mechanism dedi- genus Neurospora is consistent with a role viral defense mechanism would have cated to the protection of cells against for MSUD in speciation.

resulted from the use of short RNAs derived transposons, because it can detect and 1. Wu, C.T & Morris, J.R. Curr. Opin. Genet. Dev. 9, from the degradation of dsRNA. These rec- silence newly acquired sequences that are 237–246 (1999). ognize, by base pairing, other RNA species present as a single copy and thus unpaired 2. Shiu, P.K., Raju, N.B., Zickler, D. & Metzenberg, R.L. Cell 107, 905–916 (2001). that are homologous to the dsRNA and during meiosis prophase. Although there 3. Aramayo, R. & Metzenberg, R.L. Cell 86, 103–113 degrade them. The considerable advantage is as yet no evidence that a similar process (1996). 4. Cogoni, C. & Macino, G. Nature 399, 166–169 of this homology-dependent RNA degrada- occurs in diploid organisms, it can be (1999). tion process is that, starting from a few argued that meiotic silencing could be par- 5. Dalmay, T., Hamilton, A., Rudd, S., Angell, S. & Baulcombe, D.C. Cell 101, 543–553 (2000). dsRNA molecules, cells can generate a ticularly effective in controlling mobile 6. Mourrain, P. Cell 101, 533–542 (2000). response directed against many single- DNA elements that are frequently active in 7. Smardon, A. Curr. Biol. 10, 169–178 (2000). 8. Bernstein, E., Caudy, A.A., Hammond, S.M. & stranded viral RNAs and arrest viruses early the animal germ line and are able to trans- Hannon, G.J. Nature 409, 363–366 (2001). © http://genetics.nature.com Group 2002 Nature Publishing in their infection cycle. This mechanism pose at or near the time of meiosis. 9. Elbashir, S.M., Lendeckel, W. & Tuschl, T.Genes Dev. 15, 188–200 (2001). could be particularly useful to prevent 10. Hammond, S.M., Boettcher, S., Caudy, A.A., retroviruses, whose genomes are integrated Genome stability and speciation Kobayashi, R. & Hannon, G.J. Science 293, 1146–1150 (2001). into the genome, from successfully exiting Owing to its ability to scan the entire 11. Waterhouse, P.M., Wang, M.B. & Lough, T. Nature their latent phase and completing their lytic genome for unpaired DNA fragments, 411, 834–842 (2001). 12. Bingham, P.M. Cell 90, 385–387 (1997). cycle. The ability to control mobile DNA MSUD can be considered to be a mecha- 13. Cogoni, C. & Macino, G. Curr. Opin. Genet. Dev. 10, elements, such as transposons, by post- nism committed to maintaining genome 638–643 (2000).

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