Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Molecular Cell Biology

Language

English (en)

Date of Award

1-1-2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Susana Gonzalo

Abstract

A-type lamins, key structural components of the nucleus, have been implicated in the maintenance of nuclear architecture and chromatin organization. Mutations in A-type lamins have been associated with defects in a number of nuclear processes, including DNA replication and repair, and gene transcription and silencing. In support of an important role for nuclear organization in pathogenesis, mutations in A-type lamins are associated with a wide variety of degenerative diseases which range from muscular dystrophies and lipodystrophies to premature aging syndromes. In addition, alterations in the expression of A-type lamins are associated with different cancers such as small cell lung carcinoma and gastrointestinal neoplasms. Despite the prevalent link between A-type lamins and disease, the molecular mechanisms behind lamins-associated pathogenesis are poorly understood. Elucidation of these mechanisms would provide insight into how nuclear organization affects genome function and stability and the relationship between nuclear organization, cancer and other age-related diseases. To advance the field, I have investigated the role of A-type lamins in the maintenance of genomic stability in mammalian cells. I present data showing novel functions for A-type lamins in the maintenance of the structure and nuclear distribution of telomeres, and the efficacy of the two major pathways of DNA double strand breaks repair, non-homologous end-joining: NHEJ) and homologous recombination: HR). Furthermore, I show that the mechanisms by which A-type lamins contribute to NHEJ and HR are distinct. A-type lamins maintain post-translational stabilization of 53BP1, which is an important NHEJ protein. In addition, A-type lamins maintain HR by regulating transcription of BRCA1 and RAD51, two essential HR factors. Importantly, the study of A-type lamins has led us to the discovery of a cysteine protease, cathepsin L, as a novel regulator of 53BP1 and the retinoblastoma tumor suppressor proteins. These findings are significant, because they reveal unexpected functions of A-type lamins and novel pathways that affect genomic stability. Our findings represent an important advance in understanding how nuclear organization affects genome function.

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Permanent URL: http://dx.doi.org/10.7936/K7V40S6K

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