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Biomedicine Seminar

Andreas Ivessa, PhD, presents the work of his research group: "Investigating the mechanisms why nuclear genomic instability increases in aging cells"

19.11.2018 | Zitta Glattrup Nygaard

Dato fre 23 nov
Tid 12:00 13:00
Sted The Physiology Auditorium, build. 1162-013
Tilmelding er lukket

Abstract
The frequency of DNA breaks and number of large-scale chromosomal alterations increase during aging in various species (including yeast). Fragile chromosomal sites may have a role in these changes. Replication forks at fragile sites may break during aging because of increasing replication stress. Replication stress can be caused by pausing/stalling of replication at secondary DNA structures, topological constraints or DNA-bound proteins at the fragile sites. We and others demonstrated that non-histone protein complexes, which bind to some fragile sites (e.g., tRNA genes), cause replication pausing/stalling.

We investigated, how various fragile sites (e.g., ribosomal DNA (rDNA), tRNA genes) are replicated in young and replicative-aged yeast cells using agarose 2D gels. As expected, we observed some replication pausing/stalling at the 5S rDNA and several tRNA genes in young cells (cartoon, left side). Since nuclear genomic instability (including DNA breakage) increases with age[1], we predicted an increase in replication pausing/stalling at the tested fragile sites in old cells which may then lead to increased DNA breakage at these locations. However, to the contrary we observed that replication pausing/stalling at the fragile sites decreased in old cells (cartoon, right side).[2] We also discovered that members of the non-histone protein complexes (e.g., TFIIIC), which bind to the fragile sites (e.g., tRNA genes) in young cells, have rather a cytosolic localization and do not occupy the tested fragile sites in old cells.[2] These results agree with previous observations that the nuclear protein import efficiency decreases during aging.[3] The reduced presence of the protein complexes at the fragile sites may result in a decrease in replication pausing/stalling at these locations.

HYPOTHESIS: Since replication moves with less impediments past the fragile sites in replicative aging cells, DNA may break with lower rates at these sites. However, since as previously reported nuclear DNA breakage increases genome-wide at unknown sites with age[1], we hypothesize that DNA breaks preferentially at alternative sites in old cells. This process may influence the events that lead to increased rates of chromosomal alterations in aging cells.

In current and future directions we investigate where chromosomal DNA breaks in aging cells and whether fragile sites have a role in the age-dependent increase in nuclear genomic instability.

Venue: The Physiology Auditorium, build. 1162-013.

The talk will be of 45 min duration followed by 15 minutes of discussion.

It is possible to sign-up for a free sandwich before Wednesday, 21 November.

The Biomedicine Seminar Organizing Committee
Line Reinert
Martin Thomsen
Søren Degn
Mikkel Vendelbo

Seminar, Forskning, Ph.d.-studerende, Institut for Biomedicin, Obligatorisk for alle medarbejdere, Institut for Biomedicin, Teknisk/administrativ medarbejder, Videnskabelig medarbejder