1. Chromosomal Miss-Segregation and DNA damage Consolato Sergi, M.D., Ph.D. University of Alberta Hospital

2. Chromosomal Miss-segregation and DNA Damage

3. The Scientist September 29, 2011

4. Chromosomal Miss-segregation and DNA Damage The Scientist September 29, 2011

5. Chromosomal Miss-segregation and DNA Damage Tumor formation may require fewer steps to get started than previously thought!!! There was a missing link between chromosome instability (CIN) and DNA damage, which has been RECENTLY found! Two tumorigenesis triggers typically considered independent phenomena—can arise from a single defect in how chromosomes segregate during cell division.

6. Chromosomal Miss-Segregation and DNA Damage It is important to remind that to divide normally, cells must ensure that their chromosomes (# and structure) properly segregate, with each daughter cell receiving a copy of the duplicated chromosomes (mitosis). In the paper the authors noticed that most tumor cells exhibited both aneuploidy and structural DNA damage.

7. Chromosomal Miss-Segregation and DNA Damage Aneuploidy: Chromosomal abnormality constituted by an abnormal number of chromosomes Aneuploidy occurring in products of conception may cause genetic disorders (birth defects) Aneuploidy occurring in somatic cells can give rise to cancer.

8. Chromosomal Miss-Segregation and DNA Damage In aneuploidy there is the possibility that in the missing chromosome contains a gene encoding a protein important for DNA repair. Thus, it may lead indirectly to DNA damage!!!

9. Chromosomal Miss-Segregation and DNA Damage The authors noticed that DNA damage sometimes occurred within a single division following chromosome miss-segregation, before the daughter cells would need to start synthesizing new DNA repair proteins. Thus, this leads to hypothesize that miss-segregation is directly correlated to damaged DNA.

10. Chromosomal Miss-Segregation and DNA Damage Janssen et al. Science 2011

11. Chromosomal Miss-Segregation and DNA Damage 1.To cause aneuploidy in dividing human epithelial cells the authors treated them with a chemical that causes spindle fibers to connect a single centromere to both poles of the cell, so that the fibers would not properly split the paired chromosomes. 2.Within hours after division occurred, real-time videos tracking fluorescent staining for DNA damage showed a miss-segregation event correlated with higher levels of DNA damage.

12. Take Home Message 1.Two tumorigenesis triggers typically considered independent phenomena—can arise from a single defect in how chromosomes segregate during cell division. 2.In aneuploidy there is the possibility of a missing chromosome containing a gene encoding a protein important for DNA repair that may lead indirectly to DNA damage!!! 3.In the future we could develop anti-cancer therapeutics that target chromosome miss-segregation as a central event in the development of both abnormal chromosome number and structural DNA damage.