Early region 1A (E1A) protein is the first protein expressed following viral infection. E1A proteins initiate the cell cycle in infected cell by altering cellular gene expression and also activate expression of other viral genes enabling viral replication. The C-terminus of E1A is the least-characterized region of the protein, with few known binding partners, however DREF has been identified as a novel binding partner. My studies have determined that DREF directly binds to E1A and has a role in the virus life cycle. DREF is a restriction factor for virus growth and is a component of viral replication centres. DREF is SUMOylated and SUMOylation appears to affect localization to viral replication centres. DREF co-localizes with PML bodies and subcellular distribution of DREF is altered by the presence of E1A. This work provides a platform to study the role of DREF in uninfected cells, and in HAdV biology and its possible role in antiviral response. / October 2015

TRF1, telomeric-repeat binding factor 1, is a component of the six-subunit protein complex, referred to as shelterin, which is essential for not only regulating telomere length maintenance but also protecting mammalian telomeres from being recognized as damaged DNA. TRF1 acts as a negative mediator of telomerase-dependent telomere elongation in telomerase-expressing cells, whereas it promotes alternative lengthening of telomeres (ALT) activity by regulating ALT features including the production of extrachromosomal telomere-repeat (ECTR) DNA such as C-circles, and ALT-associated promyelocytic leukemia bodies, or APBs. The activity of TRF1 is tightly regulated by post-translational modification such as phosphorylation. This thesis sets out to investigate the function of TRF1 phosphorylation on threonine-271 (T271) and threonine-371 in telomere maintenance. The results presented in this thesis demonstrate that TRF1 phosphorylation on T271 positively regulates the association of TRF1 to telomeric DNA in telomerase expressing cells. In ALT cells, TRF1 phosphorylation on both T271 and T371 is shown to be important for the formation of APBs. Furthermore, the work presented here suggests that transcription-associated DNA damage mediates the association of phosphorylated (pT371)TRF1 with APBs. / Thesis / Master of Science (MSc) / TRF1, telomeric-repeat binding factor 1, is a component of the shelterin complex, which is essential for regulating telomere length maintenance and protecting mammalian telomeres from being recognized as damaged DNA. TRF1 acts as a negative mediator of telomerase-dependent telomere elongation in telomerase-expressing cells, whereas it promotes alternative lengthening of telomeres. The activity of TRF1 is tightly regulated by phosphorylation. This thesis sets out to investigate the function of TRF1 phosphorylation on threonine-271 and threonine-371 in telomere maintenance. Understanding how post-translational modifications on TRF1 may be linked to telomere homeostasis will be crucial for our understanding in cancer cell biology.