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W4239743178 abstract "CENP-A is a centromere-specific histone variant that determines centromere identity, but how it localizes to centromeres is not completely understood. Previously, we demonstrated that CENP-A deposition at the centromere requires ubiquitylation on lysine 124 (K124) mediated by the CUL4A-RBX1-COPS8 E3 ligase (Niikura et al., 2015Niikura Y. Kitagawa R. Ogi H. Abdulle R. Pagala V. Kitagawa K. Dev. Cell. 2015; 32: 589-603Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). A K124R mutation reduced interaction with HJURP (a CENP-A-specific histone chaperone) and abrogated centromeric localization, but addition of a mono-ubiquitin at the C terminus of CENP-A K124R restored interaction with HJURP and centromeric localization (Niikura et al., 2015Niikura Y. Kitagawa R. Ogi H. Abdulle R. Pagala V. Kitagawa K. Dev. Cell. 2015; 32: 589-603Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar), indicating that “signaling” ubiquitylation is required for CENP-A deposition at centromeres. We also showed that the CUL4A-RBX1 complex is required for loading newly synthesized CENP-A and maintaining preassembled CENP-A at centromeres by using the SNAP-tagged CENP-A system (Niikura et al., 2015Niikura Y. Kitagawa R. Ogi H. Abdulle R. Pagala V. Kitagawa K. Dev. Cell. 2015; 32: 589-603Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). Recently, we found that pre-existing ubiquitylated CENP-A is necessary for recruitment of newly synthesized CENP-A to the centromere and that CENP-A ubiquitylation is inherited through dimerization during cell division (Niikura et al., 2016Niikura Y. Kitagawa R. Kitagawa K. Cell Rep. 2016; 15: 61-76Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar). Futhermore, overexpression of mono-ubiquitylated CENP-A creates ectopic functional centromeres (neocentromeres) and causes HJURP accumulation at non-centromeric regions (Niikura et al., 2016Niikura Y. Kitagawa R. Kitagawa K. Cell Rep. 2016; 15: 61-76Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar). Thus, we proposed that CENP-A ubiquitylation determines centromere location through dimerization (Niikura et al., 2016Niikura Y. Kitagawa R. Kitagawa K. Cell Rep. 2016; 15: 61-76Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar). Fachinetti et al., 2017Fachinetti D. Logsdon G.A. Abdullah A. Selzer E.B. Cleveland D.W. Black B.E. Dev. Cell. 2017; 40 (this issue): 104-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar now report “negative” results, disputing the phenotypes that we and Yu et al. reported independently (Niikura et al., 2015Niikura Y. Kitagawa R. Ogi H. Abdulle R. Pagala V. Kitagawa K. Dev. Cell. 2015; 32: 589-603Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, Yu et al., 2015Yu Z. Zhou X. Wang W. Deng W. Fang J. Hu H. Wang Z. Li S. Cui L. Shen J. et al.Dev. Cell. 2015; 32: 68-81Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar). They report that the CENP-A S68Q and K124R mutants do not show any defects. However, we believe that the lack of proper controls may explain the discrepancy between their results and ours. We focus the remainder of our response on the K124R mutants. Fachinetti et al., 2017Fachinetti D. Logsdon G.A. Abdullah A. Selzer E.B. Cleveland D.W. Black B.E. Dev. Cell. 2017; 40 (this issue): 104-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar criticize our use of an “overexpression system” to characterize K124 ubiquitylation. However, we did detect CENP-A ubiquitylation at the endogenous level (Figure S7 in Niikura et al., 2015Niikura Y. Kitagawa R. Ogi H. Abdulle R. Pagala V. Kitagawa K. Dev. Cell. 2015; 32: 589-603Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). Furthermore, we showed that the Cul4A-Rbx1-COPS8 E3 ligase complex ubiquitylates CENP-A in vivo and in vitro (Niikura et al., 2015Niikura Y. Kitagawa R. Ogi H. Abdulle R. Pagala V. Kitagawa K. Dev. Cell. 2015; 32: 589-603Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar) and that endogenous CENP-A does not localize to the centromere properly in Cul4A-depleted or Rbx1-depleted cells. Although it is possible that depletion of Cul4A or Rbx1 proteins affects other cellular activities, the addition of mono-ubiquitin to CENP-A-K124R suppressed the defect in centromere localization in Cul4A-depleted or Rbx1-depleted cells, consistent with the idea that the loss of CENP-A ubiquitylation caused the centromere localization defects (Niikura et al., 2015Niikura Y. Kitagawa R. Ogi H. Abdulle R. Pagala V. Kitagawa K. Dev. Cell. 2015; 32: 589-603Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). Furthermore, Fachinetti et al., 2017Fachinetti D. Logsdon G.A. Abdullah A. Selzer E.B. Cleveland D.W. Black B.E. Dev. Cell. 2017; 40 (this issue): 104-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar also use overexpression in their experiments (Figures 1 and 3 in Fachinetti et al., 2017Fachinetti D. Logsdon G.A. Abdullah A. Selzer E.B. Cleveland D.W. Black B.E. Dev. Cell. 2017; 40 (this issue): 104-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). In their RPE-1 CENP-A -/F knockout (KO) system (Figure 1 in Fachinetti et al., 2017Fachinetti D. Logsdon G.A. Abdullah A. Selzer E.B. Cleveland D.W. Black B.E. Dev. Cell. 2017; 40 (this issue): 104-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar), the 5′ LTR promoter (the retroviral promoter) was used to complement the KO cells. This “moderate” overexpression of mutant proteins might still suppress the mutant phenotype, especially if the mutation causes a defect in protein-protein interactions. As described previously, the binding of CENP-A K124R to HJURP is weaker than that of wild-type CENP-A, but the mutant is still able to bind to HJURP (Niikura et al., 2015Niikura Y. Kitagawa R. Ogi H. Abdulle R. Pagala V. Kitagawa K. Dev. Cell. 2015; 32: 589-603Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). Thus, it is not surprising that an increased amount of K124R can suppress the mutant defects under some conditions (Figure 1H in Fachinetti et al., 2017Fachinetti D. Logsdon G.A. Abdullah A. Selzer E.B. Cleveland D.W. Black B.E. Dev. Cell. 2017; 40 (this issue): 104-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar indicates that EYFP-K124R was expressed at levels a few times greater than that of wild-type EYFP). Mutant proteins were also overexpressed from a CMV promoter in the LacO array-LacI-CENP-A (LacO/I) system (Figure 3 in Fachinetti et al., 2017Fachinetti D. Logsdon G.A. Abdullah A. Selzer E.B. Cleveland D.W. Black B.E. Dev. Cell. 2017; 40 (this issue): 104-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). Moreover, the levels of mutant proteins were not evaluated by immunoblotting analyses (Fachinetti et al., 2017Fachinetti D. Logsdon G.A. Abdullah A. Selzer E.B. Cleveland D.W. Black B.E. Dev. Cell. 2017; 40 (this issue): 104-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, Logsdon et al., 2015Logsdon G.A. Barrey E.J. Bassett E.A. DeNizio J.E. Guo L.Y. Panchenko T. Dawicki-McKenna J.M. Heun P. Black B.E. J. Cell Biol. 2015; 208: 521-531Crossref PubMed Scopus (73) Google Scholar). Because expression levels greatly affect the ectopic incorporation and function of CENP-A (Bodor et al., 2014Bodor D.L. Mata J.F. Sergeev M. David A.F. Salimian K.J. Panchenko T. Cleveland D.W. Black B.E. Shah J.V. Jansen L.E. eLife. 2014; 3: e02137Crossref Scopus (141) Google Scholar), a meaningful comparison requires “normalization” of CENP-A levels not done in these studies. Another caveat of the RPE-1 CENP-A -/F KO system (Figure 1 in Fachinetti et al., 2017Fachinetti D. Logsdon G.A. Abdullah A. Selzer E.B. Cleveland D.W. Black B.E. Dev. Cell. 2017; 40 (this issue): 104-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar) is that the EYFP-fusion protein is much larger than endogenous CENP-A (∼45 kDa versus ∼15 kDa). Although this CENP-A fusion does not affect the viability of “cancerous (artificially immortalized)” cells expressing the mutant proteins (Fachinetti et al., 2017Fachinetti D. Logsdon G.A. Abdullah A. Selzer E.B. Cleveland D.W. Black B.E. Dev. Cell. 2017; 40 (this issue): 104-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar), it may not faithfully recapitulate the precise endogenous regulation of CENP-A by post-translational modifications. Based on structural predictions, K124 ubiquitin does not bind directly to HJURP. Rather, the addition of mono-ubiquitin likely affects protein conformation. The presence of EYFP, a large fusion protein, may similarly affect protein conformation, perhaps mimicking the structural changes caused by ubiquitylation. Similarly, in the SNAP-tagged CENP-A system (Figure 2 in Fachinetti et al., 2017Fachinetti D. Logsdon G.A. Abdullah A. Selzer E.B. Cleveland D.W. Black B.E. Dev. Cell. 2017; 40 (this issue): 104-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar), the SNAP-tagged fusion protein was much larger than wild-type CENP-A (∼24 kDa versus ∼16 kDa), which could again induce a conformational change in CENP-A. Interestingly, Fachinetti et al., 2017Fachinetti D. Logsdon G.A. Abdullah A. Selzer E.B. Cleveland D.W. Black B.E. Dev. Cell. 2017; 40 (this issue): 104-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar report a significant difference in viability between cells expressing wild-type CENP-A and those expressing the K124R mutant (Figure 1E in Fachinetti et al., 2017Fachinetti D. Logsdon G.A. Abdullah A. Selzer E.B. Cleveland D.W. Black B.E. Dev. Cell. 2017; 40 (this issue): 104-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). Considering that endogenous CENP-A is stable for as long as 7 days after the induction of Ad-Cre (Fachinetti et al., 2013Fachinetti D. Folco H.D. Nechemia-Arbely Y. Valente L.P. Nguyen K. Wong A.J. Zhu Q. Holland A.J. Desai A. Jansen L.E. Cleveland D.W. Nat. Cell Biol. 2013; 15: 1056-1066Crossref PubMed Scopus (182) Google Scholar), the 25% reduction in mutant cell viability is significant. In the long-term viability assay (Figure 1F in Fachinetti et al., 2017Fachinetti D. Logsdon G.A. Abdullah A. Selzer E.B. Cleveland D.W. Black B.E. Dev. Cell. 2017; 40 (this issue): 104-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar), cells surviving after 100 generations could represent reversions of the original mutation or suppression by secondary mutations. Intriguingly, the number of micronuclei increased by approximately 50% in the K124R cells (Figure 1J in Fachinetti et al., 2017Fachinetti D. Logsdon G.A. Abdullah A. Selzer E.B. Cleveland D.W. Black B.E. Dev. Cell. 2017; 40 (this issue): 104-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar), suggesting that the cells were deficient in chromosome segregation at some point. Regarding suppression, we have shown that addition of a mono-ubiquitin to the C-terminal end of CENP-A K124R can suppress the mutant phenotype (Niikura et al., 2015Niikura Y. Kitagawa R. Ogi H. Abdulle R. Pagala V. Kitagawa K. Dev. Cell. 2015; 32: 589-603Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). Thus, we know that the ubiquitin group can function at different positions. When CENP-A K124R is maintained in a cell for a certain period of time, one of the other six lysines in CENP-A could be ubiquitylated, and this ubiquitylation can suppress the defects of the mutant, which may explain “surviving” cells. We have shown that the Cul4A-Rbx1-COPS8 E3 enzyme ubiquitylates CENP-A K124 (Niikura et al., 2015Niikura Y. Kitagawa R. Ogi H. Abdulle R. Pagala V. Kitagawa K. Dev. Cell. 2015; 32: 589-603Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). In their SNAP-tagged CENP-A system (Figure 2 in Fachinetti et al., 2017Fachinetti D. Logsdon G.A. Abdullah A. Selzer E.B. Cleveland D.W. Black B.E. Dev. Cell. 2017; 40 (this issue): 104-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar), Fachinetti et al., 2017Fachinetti D. Logsdon G.A. Abdullah A. Selzer E.B. Cleveland D.W. Black B.E. Dev. Cell. 2017; 40 (this issue): 104-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar used the Cul1-Rbx1-TIR1 E3 enzyme (Holland et al., 2012Holland A.J. Fachinetti D. Han J.S. Cleveland D.W. Proc. Natl. Acad. Sci. USA. 2012; 109: E3350-E3357Crossref PubMed Scopus (180) Google Scholar) to ubiquitylate EGFP-AID-CENP-A. Thus, especially in this system, it is plausible that ubiquitylation activity is increased and that CENP-A K124R could be ubiquitylated at another site. In immunofluorescence experiments (Figure 1C in Fachinetti et al., 2017Fachinetti D. Logsdon G.A. Abdullah A. Selzer E.B. Cleveland D.W. Black B.E. Dev. Cell. 2017; 40 (this issue): 104-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar), Fachinetti et al., 2017Fachinetti D. Logsdon G.A. Abdullah A. Selzer E.B. Cleveland D.W. Black B.E. Dev. Cell. 2017; 40 (this issue): 104-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar counted “positive” centromeres instead of quantifying signals of CENP-A at the centromere; this counting could fail to detect mislocalization of CENP-A. Also, Fachinetti et al. claim that their system should have no fixation artifacts because proteins were labeled fluorescently in living cells. However, the cells were later fixed for CENP-A and tubulin staining. Thus, it remains possible that the authors failed to find an optimal fixation condition to see the phenotypes that Yu et al. and our group observed and reported (Niikura et al., 2015Niikura Y. Kitagawa R. Ogi H. Abdulle R. Pagala V. Kitagawa K. Dev. Cell. 2015; 32: 589-603Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, Yu et al., 2015Yu Z. Zhou X. Wang W. Deng W. Fang J. Hu H. Wang Z. Li S. Cui L. Shen J. et al.Dev. Cell. 2015; 32: 68-81Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar). In addition, positive controls were missing in some assays in Fachinetti et al., 2017Fachinetti D. Logsdon G.A. Abdullah A. Selzer E.B. Cleveland D.W. Black B.E. Dev. Cell. 2017; 40 (this issue): 104-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar. For example, in Figure 2C of Fachinetti et al., 2017Fachinetti D. Logsdon G.A. Abdullah A. Selzer E.B. Cleveland D.W. Black B.E. Dev. Cell. 2017; 40 (this issue): 104-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, the CENP-A alpha2.2 mutant behaved as a null and served as a negative control. However, a positive control, e.g., a point mutant that is stable but deficient in centromere function, is lacking. Such a positive control was also lacking in experiments testing whether mutant CENP-A proteins are efficiently assembled at centromeres during the G1 phase of the cell cycle. Here, Fachinetti et al., 2017Fachinetti D. Logsdon G.A. Abdullah A. Selzer E.B. Cleveland D.W. Black B.E. Dev. Cell. 2017; 40 (this issue): 104-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar measured TMR-Star versus CENP-A signals at the centromere in a SNAP assay (Figure 2H in Fachinetti et al., 2017Fachinetti D. Logsdon G.A. Abdullah A. Selzer E.B. Cleveland D.W. Black B.E. Dev. Cell. 2017; 40 (this issue): 104-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar), reporting no difference in centromere propagation between wild-type and mutants. But why were TMR-Star signals normalized to CENP-A signals at the centromere? The TMR-Star signals are detected at a time point when wild-type CENP-A (EGFP-AID-CENP-A) is degraded (Figure 2C in Fachinetti et al., 2017Fachinetti D. Logsdon G.A. Abdullah A. Selzer E.B. Cleveland D.W. Black B.E. Dev. Cell. 2017; 40 (this issue): 104-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). Thus, most, if not all, of CENP-A in the cells was SNAP-tagged mutant CENP-A, and the ratio of TMR-Star-to-CENP-A signal is thus 1. Indeed, their results are 1 in all three cases (Figure 2H in Fachinetti et al., 2017Fachinetti D. Logsdon G.A. Abdullah A. Selzer E.B. Cleveland D.W. Black B.E. Dev. Cell. 2017; 40 (this issue): 104-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). A positive control, e.g., a point mutant that is stable but deficient in centromere function, would likely also yield a normalized value of 1 in this assay. Therefore, these results do not resolve whether K124 ubiquitylation is required for efficient centromere propagation. Finally, the authors used the LacO/I system to test the function of K124R during early events in centromere establishment (Figure 3 in Fachinetti et al., 2017Fachinetti D. Logsdon G.A. Abdullah A. Selzer E.B. Cleveland D.W. Black B.E. Dev. Cell. 2017; 40 (this issue): 104-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar), concluding that the K124R mutant interacts normally with HJURP. However, in our hands, with the same system, the K124R mutant shows defects in recruiting HJURP (Niikura et al., 2016Niikura Y. Kitagawa R. Kitagawa K. Cell Rep. 2016; 15: 61-76Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar). Furthermore, the mono-ubiquitin fusion protein CENP-A K124R-Ub(K48R) recruits more HJURP in this system (Niikura et al., 2016Niikura Y. Kitagawa R. Kitagawa K. Cell Rep. 2016; 15: 61-76Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar). We found that CENP-A K124R interacts with HJURP inefficiently in vivo and that mono-ubiquitylated CENP-A interacts with HJURP more efficiently in vitro (Niikura et al., 2015Niikura Y. Kitagawa R. Ogi H. Abdulle R. Pagala V. Kitagawa K. Dev. Cell. 2015; 32: 589-603Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). Results obtained by different methods are consistent with those from the LacO/I system (Niikura et al., 2016Niikura Y. Kitagawa R. Kitagawa K. Cell Rep. 2016; 15: 61-76Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar). In conclusion, given the caveats discussed above, we believe that the results of Fachinetti et al., 2017Fachinetti D. Logsdon G.A. Abdullah A. Selzer E.B. Cleveland D.W. Black B.E. Dev. Cell. 2017; 40 (this issue): 104-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar are insufficient to refute our own recent results (Niikura et al., 2015Niikura Y. Kitagawa R. Ogi H. Abdulle R. Pagala V. Kitagawa K. Dev. Cell. 2015; 32: 589-603Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, Niikura et al., 2016Niikura Y. Kitagawa R. Kitagawa K. Cell Rep. 2016; 15: 61-76Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar). Dynamic Phosphorylation of CENP-A at Ser68 Orchestrates Its Cell-Cycle-Dependent Deposition at CentromeresYu et al.Developmental CellDecember 31, 2014In BriefCENP-A Ser68 is a critical regulatory site for CENP-A recognition of its chaperone, HJURP. The dynamic phosphoregulation of Ser68 is controlled by Cdk1/PP1α, allowing cell-cycle-dependent orchestration of centromeric CENP-A deposition. Full-Text PDF Open ArchiveCENP-A K124 Ubiquitylation Is Required for CENP-A Deposition at the CentromereNiikura et al.Developmental CellFebruary 26, 2015In BriefCENP-A is a centromere-specific histone variant that determines centromere identity, but how it localizes to centromeres is not completely understood. Niikura et al. now show that CENP-A is ubiquitinated and that ubiquitination is required for CENP-A’s interaction with the chromatin assembly factor HJURP and for CENP-A localization to centromeres. Full-Text PDF Open ArchiveCENP-A Modifications on Ser68 and Lys124 Are Dispensable for Establishment, Maintenance, and Long-Term Function of Human CentromeresFachinetti et al.Developmental CellJanuary 09, 2017In BriefCENP-A is a histone H3 variant important for centromere specification. In this Matters Arising article, using CENP-A gene replacement strategies, Fachinetti, Logsdon et al. provide evidence that the Ser68phos and Lys124ub modifications of CENP-A, previously proposed to regulate CENP-A function, are not required for long-term centromere identity, function, or maintenance. Full-Text PDF Open Archive" @default.
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W4239743178 title "CENP-A Ubiquitylation Is Required for CENP-A Deposition at the Centromere" @default.
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