Chromosome metamorphoses: on the atypical roles of condensin II

Research output: ThesisDissertation (TU Delft)

Abstract

Every human being originates from a single fertilized egg cell, continuously duplicating to form a body consisting of trillions of cells in a process known as the cell cycle. This cycle involves two major stages: interphase, where the cell prepares for division, and mitosis, where it divides into two daughter cells. The accurate duplication and distribution of DNA during this process are crucial to prevent errors like cancer development.

A cell, around 10 micrometers in diameter, contains approximately two meters of DNA, divided into 46 chromosomes. These chromosomes need to be tightly folded to fit within the cell, but during interphase, they must also be accessible for protein interactions. In mitosis, chromosomes take on the X-shape, driven by a molecular machine called condensin, part of the SMC complexes family, essential for DNA folding at different cell cycle stages.

Condensin, known for shaping mitotic chromosomes, comes in two types in humans: condensin I and condensin II. This thesis explores the functions of condensin II beyond mitotic chromosome structuring. In Chapter 3, research on 24 organisms reveals diverse chromosome organization during interphase, with condensin II influencing the transition from chromosome territories to Rabl-like organization. Removal of condensin II in human cells shifts their organization.

Chapter 4 examines the impact of condensin II removal on chromosome territories in human cells, concluding that different levels of genome organization operate independently. Removing condensin II minimally affects gene expression, suggesting chromosome territories' limited role in regulating genes.

Chapter 5 investigates how condensin II prevents Rabl-like organization and centromere clustering, finding its specific role during or after mitosis. The data indicates that condensin's role in shortening the chromosome axis is crucial in preventing centromere clusters.

Chapter 6 contextualizes findings, proposing a model on how condensin II may control interphase organization based on data from Chapters 3 to 5.

Chapter 7 shifts focus to condensin II's negative regulator, MCPH1, inhibiting condensin II in interphase. Removing MCPH1 leads to interphase condensation, affecting DNA distribution during cell division. Condensin II, typically working with topoisomerase 2, encounters difficulties in untangling DNA knots when MCPH1 is absent.

This dissertation highlights the importance of balancing condensin II, investigating the consequences of its loss and over-activation. Both scenarios significantly impact cell function, emphasizing condensin II's broader role beyond mitotic chromosome organization. The research contributes fundamental insights into condensin biology, offering potential for new discoveries in this field.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Delft University of Technology
Supervisors/Advisors
  • Rowland, B.D., Supervisor
  • Haarhuis, Judith, Advisor, External person
Award date18 Jan 2024
Print ISBNs978-94-6483-646-2
DOIs
Publication statusPublished - 2024

Keywords

  • Chromosome biology
  • Molecular biology
  • SMC complexes
  • Condensin
  • Cohesin
  • chromosome condensation
  • Genome organization
  • Chromosome

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