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Kops Research 2015 Tromer GBE Widespread Recurrent Patterns of Rapid Repeat Evolution in the Kinetochore Scaffold KNL1 Eelco Tromer1,2,3, Berend Snel3,*,y, and Geert J.P.L. Kops1,2,4,*,y 1Molecular Cancer Research, University Medical Center Utrecht, The Netherlands 2Center for Molecular Medicine, University Medical Center Utrecht, The Netherlands 3Theoretical Biology and Bioinformatics, Department of Biology, Faculty of Science, Utrecht University, The Netherlands 4Cancer Genomics Netherlands, University Medical Center Utrecht, The Netherlands *Corresponding author: E-mail: [email protected]; [email protected]. yThese authors contributed equally to this work. Accepted: July 22, 2015 Abstract The outer kinetochore protein scaffold KNL1 is essential for error-free chromosome segregation during mitosis and meiosis. A critical feature of KNL1 is an array of repeats containing MELT-like motifs. When phosphorylated, these motifs form docking sites for the BUB1–BUB3 dimer that regulates chromosome biorientation and the spindle assembly checkpoint. KNL1 homologs are strikingly different in both the amount and sequence of repeats they harbor. We used sensitive repeat discovery and evolutionary reconstruc- tion to show that the KNL1 repeat arrays have undergone extensive, often species-specific array reorganization through iterative cycles of higher order multiplication in conjunction with rapid sequence diversification. The number of repeats per array ranges from none in flowering plants up to approximately 35–40 in drosophilids. Remarkably, closely related drosophilid species have indepen- dently expanded specific repeats, indicating near complete array replacement after only approximately 25–40 Myr of evolution. We further show that repeat sequences were altered by the parallel emergence/loss of various short linear motifs, including phosphosites, which supplement the MELT-like motif, signifying modular repeat evolution. These observations point to widespread recurrent episodes of concerted KNL1 repeat evolution in all eukaryotic supergroups. We discuss our findings in the light of the conserved function of KNL1 repeats in localizing the BUB1–BUB3 dimer and its role in chromosome segregation. Key words: KNL1, kinetochore, repeat evolution, BUB1, mitosis. Introduction microtubule-binding interface of kinetochores (Foley and Mitotic chromosome segregation in eukaryotes involves the Kapoor 2012; Sacristan and Kops 2015). The focal point of capture and stable attachment of the plus ends of spindle this interplay is KNL1/CASC5/AF15q14/Blinkin (hereafter re- microtubules by all chromosomes in a manner that connects ferred to as KNL1), a largely disordered protein that recruits sister chromatids to opposing spindle poles. Large multiprotein various mitotic regulators to the kinetochore and is able to assemblies on centromeric DNA, known as kinetochores, fa- directly interact with microtubules (Welburn et al. 2011; cilitate such chromosome–spindle interactions (Santaguida Caldas and DeLuca 2014)(fig. 1). and Musacchio 2009). In addition to providing a link between Critical for KNL1’s role in ensuring high fidelity chromo- DNA and the spindle, kinetochores are the signaling hubs for some segregation is the recruitment of the paralogs BUBR1 the spindle assembly checkpoint (SAC) and the target of and BUB1 (BUBs) to the outer kinetochore. Both BUBR1 and attachment-error correction mechanisms (Santaguida and BUB1 are bifunctional proteins, being involved in the SAC as Musacchio 2009; London and Biggins 2014; Sacristan and well as in regulating stability of kinetochore–microtubule in- Kops 2015). The interplay between microtubule attachment, teractions (Bolanos-Garcia and Blundell 2011). Their roles in error-correction, and SAC signaling is centered on the KMN these processes are, however, distinct. BUBR1 is a pseudoki- network (KNL1-C, MIS12-C, and NDC80-C), an outer- nase (Suijkerbuijk et al. 2012) that is a component of a diffus- kinetochore multiprotein complex that forms the ible anaphase inhibitor (Tang et al. 2001; Sudakin et al. 2001; ß The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non- commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] Genome Biol. Evol. 7(8):2383–2393. doi:10.1093/gbe/evv140 Advance Access publication August 8, 2015 2383 Downloaded from https://academic.oup.com/gbe/article-abstract/7/8/2383/557758 by University Library Utrecht user on 03 December 2017 Tromer et al. GBE Chao et al. 2012; Han et al. 2013) and regulates stability of kinetochore, which raises the question of the significance of kinetochore–microtubule attachments by localizing the phos- the other 14 repeats. In addition, although pivotal for proper phatase PP2A-B56 to kinetochores (Suijkerbuijk et al. 2012; error-correction and SAC function, preliminary analyses hinted Kruse et al. 2013; Xu et al. 2013). BUB1 regulates error-cor- at a high degree of variation in KNL1 repeat evolution (Vleugel rection by localizing Aurora B kinase to the inner centromere et al. 2012, 2013). Although MELT-like motifs were at the through the phosphorylation of T120 on the Histone 2A tail core of repeat units of most KNL1 orthologs we analyzed, (Kawashima et al. 2010; Yamagishi et al. 2010) and likely by the remainder of the repeat sequences diverged greatly, and localizing BUBR1/PP2A to kinetochores (Johnson et al. 2004; instances were observed where even a MELT-like motif was Klebig et al. 2009; Overlack et al. 2015), yet its role in the SAC indiscernible. is less well identified (Bolanos-Garcia and Blundell 2011). We performed phylogenetic analyses to reconstruct KNL1 These two BUBs directly interact through their respective repeat evolution with the aim to understand its highly TPR (tetratricopeptide repeat) domains with two different KI divergent patterns and the possible implications for BUB motifs in the N-terminus of KNL1 (Bolanos-Garcia et al. 2011; kinetochore recruitment and chromosome segregation in Kiyomitsu et al. 2011; Krenn et al. 2012). These motifs are, eukaryotes. however, not conserved beyond vertebrates and are not es- sential for BUB kinetochore binding in human cells (Vleugel Materials and Methods et al. 2013; Krenn et al. 2014). Rather, the main BUB-recruit- ment site on KNL1 is an array of multiple so-called MELT re- Sequences peats (Met-Glu-Leu-Thr). When phosphorylated by the mitotic Classical homology searches using BLAST (Basic Local kinase MPS1, they form phospho-docking sites for BUB3/ Alignment Search Tool) failed to detect sufficient homology BUB1 dimers, hence directly ensuring localization of BUB1 for KNL1 genes. We therefore performed iterated sensitive and indirectly of BUBR1 to kinetochores (London et al. homology searches with HMMer (Eddy 2011; Finn et al. 2012; Shepperd et al. 2012; Primorac et al. 2013). 2011), using a permissive E value and bitscore cut-off to in- We and others recently reported that the MELT repeats of clude diverged homologs. Given that we detected a single human KNL1 are part of larger repeated units that contain homolog per genome we considered them orthologs. We in- (besides a central MELT-like motif) at least two other motifs cluded orthologs based on the presence of a N-terminal PP1- required for function: A T motif (Txx ;where denotes recruitment motifs (SILK/RVSF), MELT-like repeats, conserved aromatic residues), and a second phospho motif (SHT) C- regions in the C-terminus including a recently discovered RWD terminal to the MELT motif (Vleugel et al. 2013, 2015; domain (Petrovic et al. 2014), and a C-terminal coiled-coil Krenn et al. 2014). Human KNL1 has approximately 20 of region. Incompletely predicted genes were searched against these larger repeats. We showed that only six repeats are whole-genome shotgun contigs (wgs; http://www.ncbi.nlm. capable of recruiting detectable BUB proteins to the nih.gov/genbank/wgs) using tBLASTn. Significant hits were FIG.1.—KNL1 is a hub for signaling at the kinetochore–microtubule interface. Schematic representation of the domain/motif architecture of human KNL1. Phospho motifs (MELTs) in the disordered middle region of KNL1 function as binding sites for various factors involved in SAC activation and error- correction (BUB3–BUB1/BUBR1). KI1 and KI2 increase the affinity of the BUB proteins for repeat 1. In addition this region harbors a basic patch involvedin microtubule binding, as well as SILK/RVSF motifs for recruitment of PP1 phosphatase. PP1 can dephosphorylate the phospho-MELT motifs. The C-terminal region contains a tandem RWD (RING-WD40-DEAD) domain that localizes KNL1 to kinetochores and a coiled-coil that interacts with Zwint-1, a factor involved in recruiting the dynein adaptor RZZ–Spindly complex to kinetochores. 2384 Genome Biol. Evol. 7(8):2383–2393. doi:10.1093/gbe/evv140 Advance Access publication August 8, 2015 Downloaded from https://academic.oup.com/gbe/article-abstract/7/8/2383/557758 by University Library Utrecht user on 03 December 2017 Evolution of KNL1 repeats GBE manually predicted using AUGUST (Stanke et al. 2006)and Repeat arrays in KNL1 orthologs display rapid consensus GENESCAN (Burge and Karlin 1997). For the sequences that sequence evolution and extensive number changes we used in this study,
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