Pathogenic mutations in components of the SMC5/6 complex cause segmented chromosomes and mosaic variegated hyperploidy

Grange, Laura Jane ORCID: 0000-0003-0909-4341 (2023). Pathogenic mutations in components of the SMC5/6 complex cause segmented chromosomes and mosaic variegated hyperploidy. University of Birmingham. Ph.D.

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Abstract

The structural maintenance of chromosomes (SMC) complexes are a highly conserved family of ring shaped ATPases which have many important functions in maintaining genome stability. Whilst cohesin (SMC1/3) and condensin (SMC2/4) have well characterised roles in cellular division, the precise functions of SMC5/6 are less well-defined, although the complex is believed to function primarily in DNA repair and replication. SMC5/6 comprises of several subunits, including SMC6, SMC5 and a number of non-SMC elements (NSEs), six of which have been identified in yeast (Nse1-6). Whilst only four NSE subunits have been identified in human cells (NSE1-4), SLF1 and SLF2, functional paralogues of Nse5 and Nse6, have been shown to promote the recruitment of SMC5/6 to damaged chromatin. The importance of SMC5/6 for human development is highlighted by that fact that mutations in SMC5/6 complex components are associated with two separate childhood syndromes. Individuals with NSE2 variants present with primordial dwarfism, extreme insulin resistance, and primary gonadal failure, whilst patients with mutations in NSE3 exhibit structural chromosome abnormalities and pulmonary disease. In this thesis I will explore the function of SMC5/6, and its impact on human disease, further, by characterising patients with mutations in two SMC5/6 associated genes: SLF2 and SMC5. Using patient derived lymphoblastoid and fibroblast cell lines, alongside U-2-OS SLF2 CRISPR mutants, I will show that SLF2 and SMC5 promote proper replication and repair and suggest novel functions for these factors in mitosis and promoting efficient replication through G4-quadruplex DNA secondary structures.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):