Cajal bodies: where form meets function

Advanced Review

Martin Machyna, Patricia Heyn, Karla M. Neugebauer

Published Online: Oct 05 2012

DOI: 10.1002/wrna.1139

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Abstract The cell nucleus contains dozens of subcompartments that separate biochemical processes into confined spaces. Cajal bodies (CBs) were discovered more than 100 years ago, but only extensive research in the past decades revealed the surprising complexity of molecular and cellular functions taking place in these structures. Many protein and RNA species are modified and assembled within CBs, which have emerged as a meeting place and factory for ribonucleoprotein (RNP) particles involved in splicing, ribosome biogenesis and telomere maintenance. Recently, a distinct structure near histone gene clusters—the Histone locus body (HLB)—was discovered. Involved in histone mRNA 3′‐end formation, HLBs can share several components with CBs. Whether the appearance of distinct HLBs is simply a matter of altered affinity between these structures or of an alternate mode of CB assembly is unknown. However, both structures share basic assembly properties, in which transcription plays a decisive role in initiation. After this seeding event, additional components associate in random order. This appears to be a widespread mechanism for body assembly. CB assembly encompasses an additional layer of complexity, whereby a set of pre‐existing substructures can be integrated into mature CBs. We propose this as a multi‐seeding model of CB assembly. WIREs RNA 2013, 4:17–34. doi: 10.1002/wrna.1139 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA Processing > 3' End Processing RNA Export and Localization > RNA Localization

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Shared components between Cajal bodies (CB) and other known types of nuclear bodies. Many protein and RNA types accumulate within CBs. Some of them have been found also in other nuclear subcompartments either because they are in different functional complexes, or shuttle between the two compartments.

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Models for Cajal body (CB) formation. (a) CB self‐assembly via RNA seed. Upon transcriptional activation of specific loci, nascent RNA nucleates the formation of the body by recruiting specific RNA‐binding protein(s). Later, other proteins are added in non‐ordered fashion to create complete canonical CBs. (b) Self‐assembly via coilin. Each of the different RNA species nucleates its own ‘sub‐Cajal body’ (sub‐CB). Note that there is no known RNA component of gems. Sub‐CBs are then integrated into canonical CBs via binding properties of coilin protein. It is not known whether CB formation occurs by different sub CB‐components coming together simultaneously or whether sub‐CBs are pre‐formed and then fuse together, analogous to lipid droplets fusing and possibly taking advantage of proposed phase transitions.

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Overview of Cajal body (CB) functions in different steps of maturation and assembly of ribonucleoprotein complexes (RNPs). After transcription of pre‐snRNAs (U1, U2, U4, U5) by RNA‐polymerase II, m⁷G caps are loaded with cap‐binding complex (CBC). SnRNAs then enter CBs where PHAX and CRM1 are loaded to form export‐competent RNP complexes. After reaching the cytoplasm, the heptameric Sm‐ring is assembled on snRNAs, m³G is formed and 3′‐ends are trimmed. Snurportin then brings these still immature snRNPs back to nucleus where they move to CBs for modification by scaRNPs and addition of snRNP‐specific proteins. Mature snRNPs then move to the nucleoplasm where splicing occurs. After splicing, snRNPs return to CBs for reassembly into active forms. SnoRNAs and scaRNAs are transcribed by Pol II, either as individual genes or harbored within introns. They mature in CBs by associating with specific proteins and then traffic to the nucleolus to process and modify pre‐rRNA and U6 snRNA. U6 snRNA is transcribed by Pol III and, after modification possibly in the nucleolus, enters CBs to be incorporated into U4/U6.U5 tri‐snRNPs. Telomerase follows a maturation pathway similar to snoRNAs but may leave CBs to elongate chromosomal telomeres.112

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Model of histone locus body (HLB) formation in Drosophila melanogaster. (a) Histone gene cluster locus with transcriptional regulators (FLASH, Mxc), which initially assemble on the locus shortly before activation of transcription. Phosphorylation of Mxc during cell‐cycle progression promotes active histone transcription in (b). Upon active transcription, other components of the HLB assemble on the locus; here, non‐ordered assembly is shown. (c) Fully assembled HLB with the major components.

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