Genetic instability upon the loss of the tumour suppressor folliculin (FLCN)

Russell, Rachel-Ann 2019. Genetic instability upon the loss of the tumour suppressor folliculin (FLCN). PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Folliculin (FLCN) is a tumour suppressor protein with unclear cellular function. Inactivating germline mutations in FLCN lead to Birt-Hogg-Dubé (BHD) syndrome. BHD patients have an increased risk of developing renal cell carcinoma (RCC). Unlike other genetic disorders with a predisposition to RCC, BHD patients are prone to all tumour subtypes (Khoo et al. 2003; Hudon et al. 2010). FLCN acts as a classical tumour suppressor in that a ‘second-hit’, deactivating mutation in the second allele, is required for cellular transformation. FLCN has been implicated in numerous signalling pathways and cellular processes. Most notably it is involved in mTOR, AMPK and HIF signalling, mitochondrial biogenesis, autophagy and membrane trafficking (Klomp et al. 2010; Tee and Pause 2013; Dunlop et al. 2014; Yan et al. 2016a). Despite this breadth of function, its currently unclear how FLCN loss contributes to the development of RCC. Therefore, to better define the tumour suppressor role of FLCN a protein-protein interaction assay, using FLCN as bait, was carried out. This revealed that FLCN interacts with numerous proteins involved in DNA-damage response and/or cell cycle regulation. To explore this further, RNAi was used to generate FLCN knockdown in human proximal tubule kidney cells. In this study, FLCN was demonstrated to interact with DNA dependent protein kinase catalytic subunit (DNA-PKcs); the apical protein in nonhomologous end joining repair (NHEJ) of double strand DNA breaks (DSB). The association of FLCN with DNA-PKcs was shown to weaken when cells are subjected to DNA damage (via ionising radiation). As a direct consequence of FLCN knockdown evidence suggest kidney cells accumulate double-strand DNA damage. Furthermore, FLCN-deficient cells display perturbed G1/S checkpoint and it is thought these cells prematurely commit to cellular division. Ultimately, this thesis highlights a novel role of FLCN within renal cell tumorigenesis and suggests it could function to maintain genomic stability. Our basic understanding of RCC within the general population is limited. Nevertheless, genetic conditions (such as BHD) that predispose individuals to cancer, provide valuable insights into somatic tumour development. By using BHD syndrome as a model of genetic instability, further work should focus on mechanistically establishing FLCN’s role in genomic integrity and will provide valuable insight into sporadic renal cancer within the general population.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Last Modified:	17 Oct 2020 01:27
URI:	https://orca.cardiff.ac.uk/id/eprint/127609

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