2. Academic Validation
  3. A non-canonical role of the inner kinetochore in regulating sister-chromatid cohesion at centromeres

A non-canonical role of the inner kinetochore in regulating sister-chromatid cohesion at centromeres

  • EMBO J. 2024 May 7. doi: 10.1038/s44318-024-00104-6.
Lu Yan # 1,  Xueying Yuan # 1,  Mingjie Liu # 2,  Qinfu Chen 3,  Miao Zhang 1,  Junfen Xu 3,  Ling-Hui Zeng 4,  Long Zhang 1 5,  Jun Huang 1 5,  Weiguo Lu 3 5,  Xiaojing He 6,  Haiyan Yan 7,  Fangwei Wang 8 9 10 11
Affiliations

Affiliations

  • 1 Life Sciences Institute, State Key Laboratory of Transvascular Implantation Devices of the Second Affiliated Hospital of Zhejiang University School of Medicine, MOE Laboratory of Biosystems Homeostasis and Protection, Zhejiang University, Hangzhou, 310058, China.
  • 2 Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
  • 3 Department of Gynecological Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
  • 4 Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, 310015, China.
  • 5 Cancer Center, Zhejiang University, Hangzhou, 310058, China.
  • 6 Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China. hexj@hust.edu.cn.
  • 7 Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, 310015, China. yanhy@hzcu.edu.cn.
  • 8 Life Sciences Institute, State Key Laboratory of Transvascular Implantation Devices of the Second Affiliated Hospital of Zhejiang University School of Medicine, MOE Laboratory of Biosystems Homeostasis and Protection, Zhejiang University, Hangzhou, 310058, China. fwwang@zju.edu.cn.
  • 9 Department of Gynecological Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China. fwwang@zju.edu.cn.
  • 10 Cancer Center, Zhejiang University, Hangzhou, 310058, China. fwwang@zju.edu.cn.
  • 11 Zhejiang Provincial Key Laboratory of Geriatrics and Geriatrics Institute of Zhejiang Province, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China. fwwang@zju.edu.cn.
  • # Contributed equally.
PMID: 38714893 DOI: 10.1038/s44318-024-00104-6
Abstract

The 16-subunit Constitutive Centromere-associated Network (CCAN)-based inner kinetochore is well-known for connecting centromeric chromatin to the spindle-binding outer kinetochore. Here, we report a non-canonical role for the inner kinetochore in directly regulating sister-chromatid cohesion at centromeres. We provide biochemical, X-ray crystal structure, and intracellular ectopic localization evidence that the inner kinetochore directly binds cohesin, a ring-shaped multi-subunit complex that holds sister chromatids together from S-phase until anaphase onset. This interaction is mediated by binding of the 5-subunit CENP-OPQUR sub-complex of CCAN to the Scc1-SA2 sub-complex of cohesin. Mutation in the CENP-U subunit of the CENP-OPQUR complex that abolishes its binding to the composite interface between Scc1 and SA2 weakens centromeric cohesion, leading to premature separation of sister chromatids during delayed metaphase. We further show that CENP-U competes with the cohesin release factor Wapl for binding the interface of Scc1-SA2, and that the cohesion-protecting role for CENP-U can be bypassed by depleting Wapl. Taken together, this study reveals an inner kinetochore-bound pool of cohesin, which strengthens centromeric sister-chromatid cohesion to resist metaphase spindle pulling forces.

Keywords

Centromere; Cohesin; Kinetochore; Mitosis; Sister-Chromatid Cohesion.

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