Investigation of Ring Finger Protein 8 in Mammalian Physiology and Pathogenesis

While genomic stability is often viewed as a cellular shield against malignant transformation, DNA double-strand breaks (DSBs) are probably the most dangerous threat to the maintenance of a stable cellular genome. Mammalian cells have evolved a sophisticated DNA damage response (DDR) network that senses the physical existence of DNA DSBs, followed by signal propagation to repair these genetic lesions. Interestingly, DSBs are not only hazardous, but are also programmed to occur during normal physiological processes such as immunoglobulin heavy chain (IgH) class switch recombination (CSR), an important mechanism for antibody diversification and specification of immunoglobulin effector function during a humoral immune response in mammals. Through catalyzing ubiquitylation of the H2A-type histones flanking DNA DSBs, the E3 ligase Ring finger protein 8 (Rnf8) orchestrates the assembly of components of homologous recombination (HR) and nonhomologous end joining (NHEJ) repair machineries into DSB-induced foci. To examine the in vivo functions of Rnf8 during mammalian development and determine the effects of its deficiency on the development of various diseases, we generated Rnf8 knockout mouse models and elucidated the pleiotropic in vivo functions of Rnf8. Overall, this thesis highlights the physiological significance of Rnf8 in shielding against DNA DSB repair defects, genomic instability, male infertility, immunodeficiency and cancer development at the organism level.

Department dc:contributor.department

Medical Biophysics

Year dc:date.issued

2015

Author dc:creator

• Li, Li

Advisor dc:contributor.advisor

• Hakem, Razqallah

Handle dc:identifier.uri

http://hdl.handle.net/1807/77730

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/77730