Role for NIP45 in Telomere Recruitment to PML Bodies in ALT Cancer Cells

Simple item page
dc.contributor.advisorCobb, Melanie
dc.contributor.committeeMemberYu, Hongtao
dc.contributor.committeeMemberCorey, David
dc.contributor.committeeMemberScaglioni, Pier
dc.creatorFarley, Demetra Dannielle
dc.date.accessioned2013-09-18T19:09:59Z
dc.date.accessioned2014-02-19T22:03:46Z
dc.date.available2013-09-18T19:09:59Z
dc.date.available2014-02-19T22:03:46Z
dc.date.created2013-08
dc.date.issued2013-05-14
dc.date.submittedAugust 2013
dc.date.updated2013-09-18T19:05:02Z
dc.description.abstractTelomere length maintenance is critical for continued cell proliferation. The SMC5/6 complex, required for double-strand break (DSB) repair in both yeast and humans, has been implicated in the maintenance of telomere length in certain cancer cells. In the absence of active telomerase, SMC5/6 complex-dependent homologous recombination is utilized to maintain telomere length at PML bodies, a mechanism referred to as alternative lengthening of telomeres (ALT). Sumoylation of several telomere-binding proteins is required for the localization of telomeres to PML bodies in G2 phase cells (APBs). We demonstrate that NIP45, a SUMO-like domain (SLD) containing protein, also affects telomere targeting in ALT cells. Loss of endogenous NIP45 protein results in decreased localization of telomeres to PML bodies in a manner independent of the SMC5/6 complex. NIP45 stimulates telomere binding protein sumoylation, as knockdown of the NIP45 protein negatively affects their sumoylation. Importantly, the NIP45 C-terminal SUMO-like domain (SLD2) is sufficient to rescue both APB formation and telomere-binding-protein sumoylation. NIP45 localizes to PML bodies, but not telomeres, in log phase cells, yet interacts efficiently with TIN2, a sumoylatable telomere binding protein. Additionally, a fragment of NIP45 containing the functional SLD2 domain is sufficient to maintain TIN2 binding. We predict, then, that NIP45 might act to recruit telomeres to the PML bodies via its interaction with TIN2, ultimately allowing for SMC5/6 complex-dependent telomere maintenance in G2 phase cells. In keeping with this hypothesis, loss of endogenous TIN2 protein also negatively affects localization of telomeres to PML bodies, even in the presence of NIP45, supporting a requirement for the TIN2-NIP45 interaction in telomere localization to PML bodies. Through this work, we have defined a role for the NIP45 protein in ALT cancer cell telomere length maintenance, further detailing the mechanism by which telomerase-negative cancer subtypes achieve unlimited replicative potential.
dc.format.mimetypeapplication/pdf
dc.identifier.other858948535
dc.identifier.urihttp://hdl.handle.net/2152.5/1348
dc.language.isoen_US
dc.subjectTelomere Homeostasis
dc.subjectCarrier Proteins
dc.subjectNeoplasms
dc.titleRole for NIP45 in Telomere Recruitment to PML Bodies in ALT Cancer Cells
dc.type.genrethesis
dc.type.materialtext
thesis.degree.departmentGraduate School of Biomedical Sciences
thesis.degree.disciplineCell Regulation
thesis.degree.grantorUT Southwestern Medical Center
thesis.degree.levelDoctoral
thesis.degree.namePh.D.

Files

Collections

University of Texas Southwestern Medical Center