TRF1 ensures the centromeric function of Aurora-B and proper chromosome segregation

Mol Cell Biol. 2014 Jul;34(13):2464-78. doi: 10.1128/MCB.00161-14. Epub 2014 Apr 21.

Abstract

A cancer is a robustly evolving cell population originating from a normal diploid cell. Improper chromosome segregation causes aneuploidy, a driving force of cancer development and malignant progression. Telomeric repeat binding factor 1 (TRF1) has been established as a telomeric protein that negatively regulates telomere elongation by telomerase and promotes efficient DNA replication at telomeres. Intriguingly, overexpression of a mitotic kinase, Aurora-A, compromises efficient microtubule-kinetochore attachment in a TRF1-dependent manner. However, the precise role of TRF1 in mitosis remains elusive. Here we demonstrate that TRF1 is required for the centromeric function of Aurora-B, which ensures proper chromosome segregation. TRF1 depletion abolishes centromeric recruitment of Aurora-B and loosens sister centromere cohesion, resulting in the induction of merotelic kinetochore attachments, lagging chromosomes, and micronuclei. Accordingly, an absence of TRF1 in human and mouse diploid cells induces aneuploidy. These phenomena seem to be telomere independent, because a telomere-unbound TRF1 mutant can suppress the TRF1 knockdown phenotype. These observations indicate that TRF1 regulates the rigidity of the microtubule-kinetochore attachment, contributing to proper chromosome segregation and the maintenance of genomic integrity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aneuploidy
  • Animals
  • Aurora Kinase B / genetics
  • Aurora Kinase B / metabolism*
  • Cell Line
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism
  • Centromere / metabolism*
  • Chromosome Segregation*
  • HeLa Cells
  • Humans
  • Kinetochores / chemistry*
  • Mice
  • Microtubules / chemistry*
  • Mitosis / genetics
  • RNA Interference
  • RNA, Small Interfering
  • Telomeric Repeat Binding Protein 1 / genetics
  • Telomeric Repeat Binding Protein 1 / metabolism*

Substances

  • RNA, Small Interfering
  • Telomeric Repeat Binding Protein 1
  • Aurora Kinase B