Vulnerability to G - Quadruplexes in BRCA2 - Null Medulloblastoma: A Protective Role for the PIF1 Helicase

Author

Danielle L. Keahi

Date of Award

2023

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Smogorzewska Laboratory

Abstract

The reasons why cancer arises in children are not fully understood. Children with biallelic mutations in the essential DNA repair factor BRCA2 are highly predisposed to develop the most common pediatric brain cancer medulloblastoma (MB) before three years of age. Medulloblastoma is often the first malignancy in these children who have a high likelihood of developing several other cancers in their lifetime. MBs have a complex mutational landscape characterized by chromothripsis in p53-deficient tumors and a high level of somatic mutation in many other cases.We utilized a mouse model of spontaneous medulloblastoma development driven by BRCA2 loss in the central nervous system coupled with global inactivation of p53 to study the roles of BRCA2 in protecting from childhood cancer development.We endeavored to address how mutagenesis can occur in tumor-initiating cells in such a short period of time by identifying sources of DNA damage in the cell of origin of BRCA2-null MB–the cerebellar granule cell progenitors(GCPs).GCPs undergo a period of massive expansion in the postnatal cerebellum, stimulated by Sonic hedgehog (Shh) signaling as well as other mitogens and can be isolated from the cerebella of mice during this developmental window that peaks at P7. After multiple symmetric divisions, GCPs exit the cell cycle, migrate into the inner granule layer of the cerebellum, and differentiate into granule cells, the most numerous single neuron type in the brain. The critical developmental window of GCP expansion represents a state where highly proliferative GCPs are vulnerable to mutagenesis.

Comments

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

Recommended Citation

Keahi, Danielle L., "Vulnerability to G - Quadruplexes in BRCA2 - Null Medulloblastoma: A Protective Role for the PIF1 Helicase" (2023). Student Theses and Dissertations. 761.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/761