Research

We are currently studying three centromere-related processes: centromeric cohesion, kinetochore-microtubule interactions, and centromeric transcription.

1. Centromeric cohesion protection and de-protection

Timely regulation of centromeric cohesion is essential for accurate chromosome segregation. How centromeric cohesion is protected before anaphase is a major question in biology. Using human cells, we found that phosphorylation-enabled binding of Sgo1-PP2A to cohesin is essential for centromeric cohesion protection. This phospho-mediated physical interaction shields the cohesin releasing factor Wapl from binding to cohesin, and also brings PP2A to de-phosphorylate Sororin, thus antagonizing Wapl binding to cohesin. We recently identified SET as a key Sgo1 inhibitor to disable Sgo1 functions at anaphase onset, thus de-protect centromeric cohesion. We also found that the elevated levels of SET protein contribute to weak centromeric cohesion in cancer cells. We are currently exploring the further mechanisms.

1. Liu, H., Rankin, S., and Yu, H. (2013). Phosphorylation-enabled binding of SGO1-PP2A to cohesin protects sororin and centromeric cohesion during mitosis. Nat Cell Biol 15, 40-49
2. Liu, H., Jia, L., and Yu, H. (2013). Phospho-H2A and cohesin specify distinct tension-regulated Sgo1 pools at kinetochores and inner centromeres. Curr Biol 23, 1927-1933.
3. Hara, K., Zheng, G., Qu, Q., Liu, H., Ouyang, Z., Chen, Z., Tomchick, D.R., Yu, H. (2014) Structure of cohesin subcomplex pinpoints direct shugoshin-Wapl antagonism in centromeric cohesion. Nat Struct Mol Biol, 21, 864-870
4. Qu Q, Zhang Q, Yang L, Chen Y, Liu H (2019) SET binding to Sgo1 inhibits Sgo1-cohesin interactions and promotes chromosome segregation. J Cell Biol. 2019 Aug 5;218(8):2514-2528.
5. Lu Yang, Qian Zhang, Hong Liu* (2021) SET levels contributes to cohesion fatigue. Mol Biol Cell (doi/10.1091/mbc.E20-12-0778)

2. Kinetochore-Microtubule Interactions

The Ska complex localizes to both kinetochores and spindle microtubules during mitosis and plays an essential for mitotic progress. We found that Cdk1 phosphorylates Ska3 at multiple sites to promote its direct binding to the Ndc80 complex (Ndc80C), a core outer kinetochore component. this phosphorylation occurs specifically during mitosis and is required for the kinetochore localization of the Ska complex. Ska3 mutants deficient in Cdk1 phosphorylation are defective in kinetochore localization but retain microtubule localization. We propose that Ska3 phosphorylated by Cdk1 in mitosis binds to Ndc80C and recruits the Ska complex to kinetochores to establish proper kinetochore-microtubule interactions. We are currently studying the underlying mechanisms.

1. Zhang Q, Sivakumar S, Chen Y, Gao H, Yang L, Yuan Z, Yu H, and Liu H (2017) Ska3 Phosphorylated by Cdk1 Binds Ndc80 and Recruits Ska to Kinetochores to Promote Mitotic Progression. Curr Biol 27(10):1477-1484.
2. Zhang Q, Hu L, Chen Y, Tian W*, and Liu H* (2020) Multisite Phosphorylation Determines the Formation of Ska-Ndc80 Macro-complexes That Are Essential for Chromosome Segregation during Mitosis. Mol Biol Cell 31(17):1892-1903.

3. Centromeric Transcription

The centromere containing tandemly repetitive and non-coding DNA sequences is under active transcription carried out by RNA Polymerase (RNP) II. Although It has been suggested that centromeric transcription plays an important role in proper centromere functions, a lot still remains unknown. Firstly, what is the exact role of centromeric transcription in regulating chromosome segregation? Secondly, how is the centromeric chromatin epigenetically? Thirdly, are any specific trans-acting factors involved in centromeric transcription regulation? We recently found that one of the major functions of centromeric transcription is to promote centromeric cohesion. We are currently studying the epigenetic regulation of centromeric transcription and characterizing the specific trans-factors.

1. Liu, H, Qu, Q., Warrington R., Rice, A., Cheng N., and Yu, H. (2015) Mitotic Transcription Installs Sgo1 at centromeres to Coordinate Chromosome Segregation. Molecular Cell, 59(3), 426-436.
2. Palozola KC, Donahue G, Liu H, Grant GR, Becker JS, Cote A, Yu H, Raj A, Zaret KS. (2017) . Mitotic transcription and waves of gene reactivation during mitotic exit. Science, 2017 Oct 6;358(6359):119-122
3. Palozola KC, Liu H, Nicetto D, Zaret KS (2018) Low-Level, Global Transcription during Mitosis and Dynamic Gene Reactivation during Mitotic Exit. Cold Spring Harb Symp Quant Biol. 2018 Jan 18. pii: 034280.
4. Yujue Chen, Qian Zhang, Zhen Teng, and Hong Liu* (2021) Centromeric Transcription Maintains Centromeric Cohesion in Human Cells. J Cell Biol. 2021 July 5;220(7) e202008146. doi: 10.1083/jcb.202008146.