How chromosomes deal with trauma – do delayed replication and repressed transcription protect previously mis-segregated chromosomes against chromothripsis?

• Applicant: Dr. Karl-Uwe Reusswig
• Subject Area: Cell Biology ; General Genetics and Functional Genome Biology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 530433556

Cancer genomes differ dramatically from normal diploid genomes, not only through mutations but also by structural variations such as complex chromosomal rearrangements or copy number alterations. Often, such rearrangements are limited to single chromosomes and caused by chromothripsis, a mutational process that reassembles a chromosome from its randomized fragments. Previous work has elucidated the mechanism leading to chromothripsis: Errors in the segregation of a chromosome or a chromosome fragment during mitosis can lead to the formation of a micronucleus. The micronucleus physically isolates the chromosome (fragment) from the other chromosomes and impairs normal nuclear processes such as transcription and replication due to a nuclear import defect. The nuclear envelope of micronuclei is less stable and prone to spontaneous rupture. This exposes the chromosomes to the cytoplasm leading to DNA damage. Recently, our lab has demonstrated that the transient isolation of a chromosome in a micronucleus can affect this chromosome’s function in the next cell cycle even prior to chromothripsis. After reincorporation into the nucleus, such a chromosome forms a novel structure inside the nucleus that we termed “micronuclear body” (MN-body). MN-bodies are not only transcriptionally repressed but also contain persistent DNA damage. My preliminary work also shows that replication is markedly delayed in MN-bodies. The functional consequences of these changes and how they affect chromothripsis are currently unclear and the molecular mechanisms mediating these changes remain to be elucidated. Interestingly, MN-bodies share similarities with 53BP1 nuclear bodies that form from incompletely replicated chromosome segments after cell division. However, the extent of this similarity remains to be determined. I hypothesize that MN-bodies form in an attempt to protect previously mis-segregated chromosomes against chromothripsis. This project aims to provide a mechanistic understanding of how repressed transcription and delayed replication contribute to this function of MN-bodies and modulate the observed pattern of chromothripsis. In contrast to the situation in 53BP1 nuclear bodies, the large number of DNA lesions in MN-bodies may impede or overwhelm the repair attempts and ultimately be resolved incorrectly. A careful characterization of MN-bodies will determine their similarities and differences to 53BP1 nuclear bodies. Overall, this project will reveal how MN-bodies, and potentially also 53BP1 nuclear bodies, impact chromothripsis and the evolution of cancer genomes.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. David Pellman