Disruption of CDK7 signaling leads to catastrophic chromosomal instability coupled with a loss of condensin-mediated chromatin compaction

J Biol Chem. 2023 Jul;299(7):104834. doi: 10.1016/j.jbc.2023.104834. Epub 2023 May 17.

Abstract

Chromatin organization is highly dynamic and modulates DNA replication, transcription, and chromosome segregation. Condensin is essential for chromosome assembly during mitosis and meiosis, as well as maintenance of chromosome structure during interphase. While it is well established that sustained condensin expression is necessary to ensure chromosome stability, the mechanisms that control its expression are not yet known. Herein, we report that disruption of cyclin-dependent kinase 7 (CDK7), the core catalytic subunit of CDK-activating kinase, leads to reduced transcription of several condensin subunits, including structural maintenance of chromosomes 2 (SMC2). Live and static microscopy revealed that inhibiting CDK7 signaling prolongs mitosis and induces chromatin bridge formation, DNA double-strand breaks, and abnormal nuclear features, all of which are indicative of mitotic catastrophe and chromosome instability. Affirming the importance of condensin regulation by CDK7, genetic suppression of the expression of SMC2, a core subunit of this complex, phenocopies CDK7 inhibition. Moreover, analysis of genome-wide chromatin conformation using Hi-C revealed that sustained activity of CDK7 is necessary to maintain chromatin sublooping, a function that is ascribed to condensin. Notably, the regulation of condensin subunit gene expression is independent of superenhancers. Together, these studies reveal a new role for CDK7 in sustaining chromatin configuration by ensuring the expression of condensin genes, including SMC2.

Keywords: CDK7; CT7001; SMC2; THZ1; TNBC; chromosomal instability; condensin; cyclin dependent kinase 7; mitosis; mitotic catastrophe; triple negative breast cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Chromatin* / genetics
  • Chromatin* / metabolism
  • Chromosomal Instability / genetics
  • Cyclin-Dependent Kinases* / genetics
  • Cyclin-Dependent Kinases* / metabolism
  • Gene Expression Regulation / genetics
  • Gene Silencing
  • Humans
  • Mitosis / genetics
  • Signal Transduction*

Substances

  • Chromatin
  • condensin complexes
  • Cyclin-Dependent Kinases
  • CDK7 protein, human
  • SMC2 protein, human
  • Cell Cycle Proteins