Understanding of Intrinsic Sources of DNA Damage that Drive Human Disease: A Foray into the Study of DNA Interstrand Crosslinks and Genome-Embedded Ribonucleotides

Author

Nicolas Johannes Georg Blobel

Date of Award

2024

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Thesis Advisor

Agata Smogorzewska

Abstract

Sources of damage to deoxyribonucleic acid (DNA) can be categorized broadly into exogenous and endogenous. Exogenous sources range from environmental (e.g., air pollution, tobacco and alcohol, ultraviolet (UV) radiation due to sun exposure), to pharmaceutical sources (e.g., chemotherapeutics such as cisplatin). The other main category of DNA damage is endogenous, which can range from metabolites such as reactive oxygen species (ROS) produced in the cells as byproducts of metabolic pathways, to incorrect bases incorporated into the genome. In this thesis, I will focus on two types of endogenous DNA damage: 1) interstrand crosslinks (ICLs) formed by DNA damaging aldehydes and 2) genome-embedded ribonucleotides. The clinical pathologies arising in the setting of the improper removal or repair of ICLs or genome-embedded ribonucleotides are diverse. A failure to remove ICLs in humans is the cause of Fanconi anemia (FA), a disease characterized by early bone marrow failure, congenital abnormalities, and an early onset of cancers such as leukemia and head and neck squamous cell carcinomas (HNSCC). On the other hand, failure to appropriately remove genome-embedded ribonucleotides leads to Aicardi-Goutières Syndrome (AGS), a rare autosomal recessive neurological disorder, which clinically mimics a congenital viral infection. Part I of this thesis focuses on the study of the endogenous sources of ICLs in human oral keratinocytes, the precursor cell of HNSCC. Part II of this thesis concentrates on the study of the enzyme RNase H2 and its actions in ensuring genomic stability by removing genome-embedded ribonucleotides.

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

Blobel, Nicolas Johannes Georg, "Understanding of Intrinsic Sources of DNA Damage that Drive Human Disease: A Foray into the Study of DNA Interstrand Crosslinks and Genome-Embedded Ribonucleotides" (2024). Student Theses and Dissertations. 793.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/793