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Unexpected Roles of a Shugoshin Protein at Subtelomeres

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Unexpected Roles of a Shugoshin Protein at Subtelomeres Genes Genet. Syst. (2017) 92, p. 127–133 Roles of shugoshin at subtelomeres 127 Unexpected roles of a shugoshin protein at subtelomeres Junko Kanoh* Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan (Received 3 April 2017, accepted 19 June 2017; J-STAGE Advance published date: 9 August 2017) A chromosome is composed of structurally and functionally distinct domains. Telo- meres, which are located at the ends of linear chromosomes, play crucial roles in genome stability. Although substantial knowledge of telomeres has been accu- mulated, the regulation and function of subtelomeres, which are the domains adjacent to telomeres, remain largely unknown. In this review, I describe recent discoveries about the multiple roles of a shugoshin family protein, Sgo2, which is localized at centromeres in mitosis and contributes to precise chromosome segrega- tion, in defining chromatin structure and functions of the subtelomeres in fission yeast. Sgo2 becomes enriched at the subtelomeres, particularly during G2 phase, and is essential for the formation of a highly condensed subtelomeric chromatin body called the knob. Furthermore, Sgo2 maintains the expression levels of sub- telomeric genes and the timing of DNA replication at subtelomeric late origins. Key words: subtelomere, shugoshin, heterochromatin, knob, replication timing regulated remain outstanding issues. INTRODUCTION The telomere, a specialized chromatin structure at the Composition of subtelomeric DNA Telomeres are ends of chromosomes, plays important roles in genome composed of DNA with repeated sequence ([TTAGGG]n integrity, and the adjacent chromosomal region, the sub- in mammals) and its associated proteins. In contrast, telomere, has recently become a focus of attention in the subtelomeres do not possess telomere repeat sequences; medical field. Subtelomere deletion syndrome (STD) is however, they generally contain multiple segments that a congenital disease arising from deletion or rearrange- share high similarity with each other in a specific organ- ment in the subtelomeric region. STD patients exhibit ism, in addition to various genes. In budding yeast, mental retardation and multiple congenital anomalies, Saccharomyces cerevisiae, subtelomeres span approxi- which most likely develop from the haploinsufficiency of mately 25 kb and include X and Y’ elements with highly subtelomeric genes (de Vries et al., 2003). Furthermore, variable lengths. The X element contains a highly facioscapulohumeral muscular dystrophy is caused by an homologous X core region (475 bp) and an autonomously increase in the expression of the DUX4 gene, located at replicating sequence; the Y’ element contains an RNA the subtelomere, which is affected by telomere position helicase gene (Louis, 1995). Internal repeat sequences effects (Stadler et al., 2013). Therefore, maintenance of exist in some subtelomeres at the telomere-distal region subtelomeric gene expression appears to be critical for adjacent to the X’ and Y elements. The length of the human health. internal repeats is also variable; they sometimes contain Although substantial knowledge of telomeres has accu- genes encoding PAU (seripauperin multigene family), mulated, the regulation and function of subtelomeres MAL (multigene complex for maltose fermentation), MEL remain a long-term mystery: research on subtelomeres (α-galactosidase) or ERR (enolase) proteins (Louis, 1995) has been progressing much more slowly than research (Fig. 1A). In humans, subtelomeres possess a mosaic of on other chromosomal regions due to technical difficul- multiple common sequences (more than 40 types in total) ties resulting from the structural nature of subtelomeric containing various genes. The length of the homologous homologous sequences, which are very long and present regions of human subtelomeres varies from less than in large numbers of copies. In particular, how the con- 20 kb to more than 200 kb (Linardopoulou et al., 2005; densed and silenced chromatin structure at subtelomeres Riethman et al., 2005; Stong et al., 2014). is formed and how replication timing at subtelomeres is The fission yeast, Schizosaccharomyces pombe, pos- sesses three chromosomes. Although genome sequenc- ing is not yet complete, the subtelomeres of S. pombe also Edited by Kenji Ichiyanagi * Corresponding author. E-mail: [email protected] contain highly homologous sequences spanning 40–60 DOI: http://doi.org/10.1266/ggs.17-00016 kb in chromosomes 1 and 2 that harbor the RecQ-type Figure 1 Kanoh 128 J. KANOH A S. cerevisiae Internal repeats X B S. pombe Highly homologous Mosaic of Unique sequence common segments Subtelomeric homologous region Fig. 1. Composition of subtelomeres. (A) Representative structure of the subtelomeres in S. cerevisiae. (B) Structure of the subtelomeres of chromosomes 1 and 2 in S. pombe. See main text for details. helicase genes (tlh1/2 +) (http://www.pombase.org/status/ In contrast, S. cerevisiae does not possess H3K9me or sequencing-status). The telomere-proximal regions are HP1 homologs; instead, the telomere-binding protein Rap1 composed of a mosaic of common segments exhibiting associates with Sir3-Sir4 (silencing factors), which then variations like those in humans (Sugawara, 1988). The recruits Sir2, a histone deacetylase, to deacetylate his- telomere-distal regions of approximately 50 kb do not tones H3 and H4. After this, Sir3-Sir4 is again recruited contain sequences that are homologous between subtelo- to the deacetylated chromatin and again recruits Sir2, to meres. However, they share a common feature of chro- expand the heterochromatin (Huang, 2002) (Fig. 3B). matin structure: the levels of histone modifications, such Heterochromatin generally brings about a transcription- as methylation and acetylation, are very low compared ally silent state. Thus, the expression of genes located with the adjacent euchromatin and subtelomeric hetero- within subtelomeric heterochromatin is repressed; how- chromatin regions (see below) (Buchanan et al., 2009) ever, the physiological functions of these gene products (Fig. 1B and 2). The number of subtelomeres varies from remain largely unknown. Moreover, the roles of subtelo- four to six per S. pombe haploid genome, depending on meric heterochromatin itself have not yet been clarified. the presence or absence of a short subtelomereric homolo- gous sequence (approximately 15 kb) and a chromosome Sgo2 is localized at subtelomeres during inter- 3-specific sequence (1.1 kb) between the telomeres and phase Shugoshin is a well conserved centromere pro- the rDNA repeats at the ends of chromosome 3 (Ohno et tein and plays crucial roles in centromeric cohesion al., 2016). and/or proper chromosome segregation in mitosis and meiosis (Kerrebrock et al., 1995; Kitajima et al., 2004; Subtelomeric heterochromatin structure Subtelo- Marston et al., 2004; Rabitsch et al., 2004; Salic et al., meres generally include heterochromatin, where histone 2004; Kawashima et al., 2007; Vanoosthuyse et al., 2007). H3 methylated at K9 (H3K9me) is highly enriched and Schizosaccharomyces pombe possesses two shugoshin heterochromatin protein 1 (HP1) homologs are associ- paralogs, Sgo1 and Sgo2. Sgo1 is expressed only dur- ated (Elgin and Grewal, 2003). At least two factors can ing meiosis and plays a critical role in centromeric cohe- independently establish subtelomeric heterochromatin in sion of sister chromatids in meiosis I (Kitajima et al., S. pombe. One is the telomere-binding protein complex 2004). In contrast, Sgo2 is continuously expressed and called shelterin; the other is the RNAi machinery, which contributes to precise chromosome segregation during acts at the centromere-homologous (cenH) sequence (the M phase (Kawashima et al., 2007). Intriguingly, it was template of siRNA) within the tlh1/2 + genes in the sub- reported that Sgo2 changes its localization from the cen- telomeres. After a methyltransferase, Clr4, methylates tromeres to the vicinity of the telomeres upon entry into H3K9 and an HP1 homolog, Swi6, is recruited to the interphase (Kawashima et al., 2010); however, detailed telomere-proximal sites, the heterochromatin spreads out information about Sgo2 localization and the physiologi- around the subtelomeric homologous regions, presumably cal roles of Sgo2 near telomeres remained unknown. In via the association of Swi6 with itself and Clr4 (Hall et the following sections, I describe our recent discovery of al., 2002; Cam et al., 2005; Kanoh et al., 2005; Wang et unexpected roles of Sgo2 at the subtelomeres in S. pombe al., 2016) (Fig. 3A). (Tashiro et al., 2016). Figure 2 Kanoh Roles of shugoshin at subtelomeres 129 Sgo2 Swi6 Swi6 Swi6 Knob Heterochromatin Low levels of Euchromatin High H3K9 methylation Telomere histone modifications Subtelomere (~100 kb) Fig. 2. Schematic illustration of the chromatin structure of S. pombe subtelomeres. Heterochromatin containing Figurehighly 3 methylated Kanoh H3K9 and Swi6 is formed around the subtelomeric homologous region (approximately 50 kb). Sgo2 associates with the whole subtelomere (approximately 100 kb), and is required for the formation of a knob (approxi- mately 50 kb) next to the heterochromatin, where various histone modifications are maintained at low levels. A euchromatin region, where gene transcription is active, is adjacent to the subtelomere. Swi6 Establishment A S. pombe of heterochromatin Swi6 Spreading of heterochromatin RNA Clr4 Clr4 Swi6 RNAi Shelterin Subtelomere siRNA template Telomere (cenH in tlh1/2) B Establishment
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