Student Theses and Dissertations

Teresa Davoli

Date of Award

2013

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

de Lange Laboratory

Abstract

Aneuploidy, i.e. the state of having an abnormal chromosome number, is a hallmark of human solid tumors. A fraction of aneuploid tumors is near-diploid and can be explained by individual chromosome gains and losses in mitosis. The remaining fraction is subtetraploid, containing an increased chromosome number, ranging from 60 to 90 chromosomes. Mounting evidence argues that tetraploidization, i.e. whole genome doubling, followed by chromosome loss is likely to represent an early event in the development of subtetraploid tumors. The origin of tetraploidization in cancer is still unclear. Here we de- scribe a new potential mechanism of tetraploidization in cancer, originating from telomere dysfunction, a widespread phenomenon in early tumorigene sis. Prolonged telomere deprotection caused by inactivation of the telomeric proteins POT1a and POT1b leads to tetraploidy in p53/Rb de cient mouse cells. Irreversible telomere deprotection and other forms of persistent DNA damage induce a prolonged G2 phase followed by by-pass of mitosis, re-entry into S phase, and whole genome reduplication. Endoreduplication requires an ATM and/or ATR-dependent DNA damage signal, blocking the activation of Cdk1/CyclinB and mitosis. Furthermore, we demonstrate tetraploidization through endoreduplication or mitotic failure in human broblasts and mammary epithelial cells undergoing replicative telomere crisis in the absence of p53 and Rb. Using an inducible system to generate transient telomere dam- age, we show that telomere-driven tetraploidization enhances the tumorigenic transformation of mouse cells. Finally we showed that breast cancer cell lines with high chromosome numbers display higher frequency of telomeric fusions compared to near-diploid lines, suggesting previous telomere crisis during their development. Collectively, these data suggest a potentially widespread mechanism for tetraploidization resulting from excessive telomere shortening in early precancerous lesions, promoting the evolution of a subtetraploid cancer karyotype.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

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