Présentation
This edition of the Paris Postdoc Seminars at Institut Pasteur will take place Tuesday, 25 June 2024, at 11:00 in the CFJ Auditorium. Teams link available.
Abstract
Aneuploidy, a condition of karyotype imbalance, is a widespread property of cancer cells: changes in chromosomal copy numbers is believed to drive cell transformation by favoring genomic instability and chromosome mis-segregation. In particular, tumors harbor a specific type of numerical and structural aneuploidy such as whole-arm chromosome gain, loss and translocations. These events are triggered by initial breakages occurring within the (peri)centromeres, unique chromosomal loci built on large stretches of repetitive sequences that play a key role in granting proper chromosomal segregation during mitosis. The propension of centromere to undergo breakage highlight an intrinsic fragility of these genomic regions. However, little is still known on the mechanisms leading to centromere fragility in cancer cells and why centromeres are hotspots for chromosomal breakage.
We delve into the causes of centromere fragility unveiling specialized replication dynamics, distinct from the rest of the genome, that are crucial for maintaining the centromeres’ integrity. We show that replication stress, hallmark of precancerous lesions, promotes centromeric ruptures in mitosis. Using an innovative locus-specific quantitative approach, we identify the molecular signature of replication stress and fragility at human centromeres, uncovering factors such as translesion synthesis polymerases that contribute to sustaining the centromere replication and therefore integrity. We show that prolonged stress causes centromeric alterations and whole-arm chromosomal translocations in tumors models of ovarian cancer cells experiencing replication stress. Overall, our findings reveal the cascade of events that initiate from centromere instability generating during perturbed DNA replication to centromeric-specific structural aneuploidy in tumor cells.
Keywords: Genome instability, DNA replication, replication stress, centromere, DNA damage
Localisation
Bâtiment: JACOB
Salle: Auditorium François JACOB
Adresse: 28 Rue du Docteur Roux, Paris, France