SP-3: A statistical modeling approach to identify common triggers for replication stress and mitotic chromosome missegregation

Maik Kschischo, Koblenz Summary Replication stress (RS) and chromosomal instability (CIN) are commonly observed features of cancer cells. RS has a destabilizing effect on the genome and, vice versa, whole chromosome aneuploidy as a result of CIN can induce a RS response. Our preliminary data analysis of cancer genomic data suggests a tendency of whole […]

SP-4: Centrosome integrity as a determinant of replication stress and mitotic dysfunction

Matthias Dobbelstein, Göttingen Summary Centrosomes are crucial in the assembly of mitotic spindles and faithful separation of chromosomes in mitosis. Like chromosomes, centrosomes need to be duplicated exactly once during the cell cycle, suggesting mutual regulation. Clinically, germ line mutations of centrosomal components lead to similar syndromes as defects in the replication stress signaling, a […]

SP-5: Impaired chromosome integrity caused by mutations in members of the BTR complex

Bernd Wollnik, Göttingen Summary Genomic instability is a shared pathogenic mechanism of selected inherited, monogenic disorders caused by mutations in genes encoding proteins with important functions for genomic maintenance. Recent advances in next-generation sequencing (NGS) technologies have allowed the identification of novel genes associated with genomic instability syndromes. However, our understanding of alterations of genomic […]

SP-6: Proteomics of mitotic inter sister chromatid junctions

Räschle Markus, Kaiserslautern Summary Replication stress is a key driver of genomic instability giving rise to human disease, for instance cancer or developmental disorders. It is caused by a variety of defects such as lesions blocking replication (e.g. DNA interstrand crosslinks) or processes that lead to the exhaustion of DNA precursors. This generates under-replicated DNA […]

SP8: The causes of replication stress in response to whole chromosomal aneuploidy

Zuzana Storchova, Kaiserslautern Summary Cancer is a disease of the genome, with both structural and numerical chromosomal aberrations, so called aneuploidy, occurring concomitantly in most tumors. Despite this co-occurrence, the advances in the characterization of point mutations and structural and numerical changes failed to provide an insight into a possible functional relationship between structural and […]

SP-Z: NGS-based approaches for systematic analysis of genomic and chromosome instability

Bernd Wollnik, Göttingen Summary The objective of the central project is providing access to state-of-the-art sequencing technology and methods as well as novel next-generation sequencing (NGS)-based approaches to all partners and individual projects within the consortium. Advances in NGS and NGS-based approaches such as whole-genome sequencing (WGS) have tremendously improved the detection of structural variants/copy […]

SP-1: Deciphering signaling pathways that promote accurate chromosome segregation after replication stress

Petra Beli, Mainz Summary To maintain genome stability, human cells depend on accurate DNA replication in S-phase and chromosome segregation in mitosis. Replication stress refers to slowing down or stalling of replication forks that occurs due to DNA lesions, R-loops or oncogene activation. One consequence of replication stress is entry of cells into mitosis with […]

SP-2: Molecular mechanisms of replication stress-induced mitotic chromosome missegregation

Holger Bastians, Göttingen Summary Structural and numerical chromosome aberrations are commonly and concomitantly detected in cancer and in age-related syndrome cells suggesting a functional relationship between structural and whole chromosome instability (S-CIN and W-CIN, respectively). Recent evidence suggests that replication stress can not only drive S-CIN and the generation of structural chromosome aberrations, but might […]