자료유형  

 학위논문

Control Number  

0017163849

International Standard Book Number  

9798384097877

Dewey Decimal Classification Number  

574

Main Entry-Personal Name  

Zych, Molly Grace.

Publication, Distribution, etc. (Imprint  

[S.l.] : University of Washington., 2024

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2024

Physical Description  

98 p.

General Note  

Source: Dissertations Abstracts International, Volume: 86-03, Section: B.

General Note  

Advisor: Hatch, Emily.

Dissertation Note  

Thesis (Ph.D.)--University of Washington, 2024.

Summary, Etc.  

요약Micronuclei (MN) form when missegregated chromatin recruits its own nuclear envelope after mitosis. MN are byproducts of genome instability, are defective in performing most nuclear functions, and cause further aneuploidy and DNA damage. MN are unstable and their rupture can activate immune signaling and metastatic pathways, contributing to cancer progression. Many studies have identified mechanisms that contribute to MN rupture. Defects in nuclear envelope protein recruitment lead to rupture and are influenced by spindle position or chromosome identity. Chromosome size influences MN stability through lamin B1 and nuclear pore complex recruitment, while gene density influences stability through lamina organization, though the mechanism behind this is not known. While most nuclear functions are altered in MN, it's still not well understood how or if these erroneous functions also contribute to MN rupture. In this work, I first investigate how gene density influences the stability of small MN, MN containing short chromosomes, in Chapter 2. I find that histone modifications are influential on small MN rupture, where heterochromatin contributes to lamina gaps and instability. This occurs through nuclear growth, which is largely influenced by nuclear transport and recruitment of RCC1, a RanGEF. Euchromatic MN, which are stable, are especially depleted for RCC1, whereas heterochromatic MN have higher RCC1 recruitment. In addition to this defect in small MN, I identify growth as a new contributor to MN rupture and find that all MN have an export defect that leads to growth, lamina gap formation, and rupture. I analyzed existing chromothripsis data from patients and found that chromothripsis on early rupturing chromosomes contains higher levels of APOBEC mutations compared to late rupturing chromosomes, suggesting rupture timing is important for MN consequences. Additional work summarized in Chapter 3 looks into the mechanisms responsible for MN formation. I determined MN content after spindle assembly checkpoint inhibition or merotelic microtubule attachment and found that MN content is non-random and specific to the mechanism of formation. Additional unfinished work developed tools to identify MN content in a high throughput manner, either through subcellular fractionation or multiplexed DNA-FISH.Together these studies help define how chromosome identity influences MN formation, function, rupture, and the consequences of MN rupture. This work suggests that the previously identified defects in MN function are more variable than previously appreciated and that these differences can influence the contribution MN make to long lasting cellular consequences. Future studies should look further into the cause of the transport defects in MN, better define what triggers MN rupture, and test the role of these mechanisms of MN rupture in vivo.

Subject Added Entry-Topical Term  

Cellular biology.

Subject Added Entry-Topical Term  

Oncology.

Subject Added Entry-Topical Term  

Biochemistry.

Subject Added Entry-Topical Term  

Genetics.

Subject Added Entry-Topical Term  

Immunology.

Index Term-Uncontrolled  

Micronuclei

Index Term-Uncontrolled  

Nuclear functions

Index Term-Uncontrolled  

Cancer progression

Index Term-Uncontrolled  

Chromothripsis

Index Term-Uncontrolled  

Heterochromatin

Added Entry-Corporate Name  

University of Washington Molecular and Cellular Biology

Host Item Entry  

Dissertations Abstracts International. 86-03B.

Electronic Location and Access  

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Control Number  

joongbu:654825