A role for hnRNPUL2 in linking the management of DNA topology with the DNA damage response

James Allen

Research output: ThesisDoctoral Thesis

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Abstract

[Truncated] The simple definition of the DNA as a repository of genetic information belies the complex systems necessary for it to achieve this function. As the storage medium of the genome, DNA must be both accessible to processes such as transcription and replication, and robust in its preservation of the information it contains. As such, sophisticated mechanisms have evolved to both manage the physical properties of the molecule as the information encoded by its sequence is stored and accessed, and to detect and repair any changes to this information. This thesis describes novel functions for heterogeneous ribonucleoprotein-U-like protein two (hnRNPUL2) in each of these processes, and suggests that the protein has a unique role at the interface of these two systems.

hnRNPUL2 is a poorly characterised protein, and its functions had not been extensively studied prior to this project. The protein was first identified as a binding partner of Myeloid leukaemia factor one (Mlf1), able to recruit Mlf1 from the cytoplasm into the nucleus, where Mlf1 functions in regulating haemopoietic lineage commitment, transcription, and the cell cycle. Additionally, earlier unpublished work performed in this laboratory identified putative interactions of hnRNPUL2 with several proteins, including topoisomerase II. This interaction was interesting because topoisomerase II is a key regulator of DNA topology as well as a chemotherapeutic drug target. Moreover, recent reports have identified hnRNPUL2 as promoting end resection during homology mediated DNA repair.

The goals of this thesis were to investigate the biological significance of the interaction between hnRNPUL2 and topoisomerase II, to discern the involvement of hnRNPUL2 in the DNA damage response, and to explore how these two functions relate to each other.

In order to predict and better explain the properties of hnRNPUL2, its protein sequence was extensively analysed. This led to the prediction and subsequent experimental validation of a chromatin binding function for the protein. Furthermore, immunofluorescence analysis revealed that hnRNPUL2 dynamically co-localises both with chromatin and with topoisomerase II over the course of the cell cycle, and that its morphology is altered by the inhibition of transcription.

Original languageEnglish
QualificationDoctor of Philosophy
Publication statusUnpublished - 2015

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