Date of Award

Summer 2023

Document Type

Open Access Thesis


Biological Sciences

First Advisor

Alan Waldman


Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic condition characterized by accelerated aging. The cause of HGPS is a point mutation in the LMNA gene, which encodes lamins A and the splice variant lamin C. Lamins are components of the nuclear lamina, a complex that plays structural and catalytic roles in the nucleus that are essential to chromatin organization, DNA replication, and DNA repair. The mutation associated with HGPS activates a cryptic splice donor site which alters the lamin A protein in a way that does not allow prelamin A to be fully processed, and ultimately results in the accumulation of a mutated, toxic lamin A protein known as “progerin.” Previous studies have shown that progerin is found at low levels in older healthy individuals. Progerin disrupts nuclear architecture and fundamental cellular processes, consequently increasing genomic instability, a major hallmark of cancer and aging. Eukaryotes have evolved various mechanisms, collectively known as the DNA damage response (DDR), that serve to repair these potentially disastrous events. The faithfulness and timeliness of DDR is crucial to maintain genomic stability and prevent catastrophic events at both the cellular and organismal level. In my thesis I show that progerin overexpression correlates with persistent DDR signaling following hydroxyurea induced stress through chronic activation. Persistent DDR signaling can be indicative of negatively altered DNA repair which can result in unrepaired or misrepaired DNA double strand breaks(DSBs), a dangeroustype of DNA damage. This may relate to the observation that individuals with HGPS rapidly accumulate DNA DSBs. An accumulation of such events can contribute to genomic instability; therefore, it is crucial that these breaks are repaired accurately and efficiently. DSB repair most often occurs through one of two pathways: homologous recombination (HR), the more accurate of the two where a template DNA strand aids repair, or by nonhomologous end-joining (NHEJ), a rejoining of DNA ends with no template, which is typically more error-prone. My work provides further support for the previous report by our lab that overexpression of progerin, but not wildtype lamin A, correlates with an increase in NHEJ relative to HR. I have also shown that progerin further alters the accuracy of DNA repair events through the use of a reporter construct to specifically monitor DNA end-joining in progerin overexpressing cells. Progerin overexpression led to a significant increase in imprecise end-joining relative to precise end-joining. Overall, the work presented in this thesis shows that progerin negatively alters genome maintenance through abnormal DDR signaling shown by increased DNA damage, decreased recovery, suppression of interactions between terminal complementary DNA sequences, and an increase in low-fidelity break repair. All of these factors contribute to progerin ultimately compromising genomic stability.


© 2023, Liza Alexandra Joudeh

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