FOR 2800:  Chromosome Instability: Cross-talk of DNA replication stress and mitotic dysfunction

• Subject Area: Biology
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 395736209

The Research Unit 2800 (FOR 2800/2) addresses the scientific question regarding the origin of chromosome instability (CIN), which causes structural as well as numerical chromosome aberrations. It is well established that CIN and increased levels of chromosome aberrations are closely associated with many human diseases including cancer, neurodegenerative diseases and age-related syndromes and can act as key drivers for disease development and progression. An important cellular condition that causes structural chromosome instability (S-CIN) and leading to structural chromosome aberrations is “replication stress”, which is characterized by a slowed-down or aberrant progression of replication forks during DNA replication in S phase of the cell cycle. On the other hand, errors during mitosis that result in chromosome missegregation are well-known causes of whole chromosome instability (W-CIN) leading to the induction and evolvement of aneuploidy. Since S-CIN and W-CIN are often, if not always, detected concomitantly in various CIN-associated diseases including cancer, the two forms of chromosomal instability might be mechanistically interlinked. In fact, recent evidence indicate that replication stress can promote mitotic chromosome missegregation and aneuploidy. Vice versa, whole chromosome aneuploidy can also contribute to replication stress, thereby establishing a vicious cycle between DNA replication stress and mitotic dysfunction. The FOR 2800 combines complementary scientific expertise on replication stress, mitotic chromosome segregation, genome instability and aneuploidy to elucidate the mechanistic links between DNA replication stress in S-phase and perturbed chromosome segregation during mitosis and vice versa. The central goal of the research unit 2800 is to define and characterize the molecular mechanisms linking structural and numerical chromosome instability, which are key drivers of human diseases and aging processes.

• DFG Programme: Research Units

Projects

• Coordination Funds (Applicant Bastians, Holger )
• Impaired chromosome integrity caused by mutations in members of the BTR complex (Applicant Wollnik, Bernd )
• Modelling the link between replication stress, chromosomal instability and aneuploidy (Applicant Kschischo, Maik )
• Mutual impact of replication origin firing regulation and mitotic chromosome segregation (Applicant Boos, Dominik )
• Proteomics of mitotic sister chromatid junctions in response to DNA replication stress (Applicant Räschle, Markus )
• SP2: Molecular mechanisms of replication stress-induced mitotic chromosome missegregation (Applicant Bastians, Holger )
• SP4: Centrosome integrity as a determinant of replication stress and mitotic dysfunction (Applicant Dobbelstein, Matthias )
• SP8: The causes of replication stress in response to whole chromosomal aneuploidy (Applicant Storchova, Zuzana )
• SP-Z: NGS-based approaches for systematic analysis of genomic and chromosome instability (Applicant Wollnik, Bernd )
• The role of R-loops in oncogene-induced replication stress and chromosomal instability (Applicant Beli, Petra )
• The role of replication stress in the development of chromosomal alterations in myelodysplastic syndrome (Applicant Flach, Johanna )

• Spokesperson: Professor Dr. Holger Bastians