Investigation into the role of the SMC5/6 complex in human cells

McGregor, Grant Alexander (2017) Investigation into the role of the SMC5/6 complex in human cells. Doctoral thesis (PhD), University of Sussex.

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Abstract

The Structural Maintenance of Chromosome (SMC) family of proteins are required to regulate almost all aspects of chromosome biology and are critical for genomic stability. The SMC5/6 complex, a member of this family, is composed of two SMC heterodimers and six additional Non-SMC Elements 1-6. The components of SMC5/6 possess activities including ATPases, ubiquitin and SUMO ligases. SMC5/6 is required in homologous recombination and for
accurate chromosome segregation. Loss of SMC5/6 is lethal in yeasts, embryonic lethal in mice and mutations in NSMCE2 leads to primordial dwarfism and insulin resistance.

This thesis focuses on a mutation in NSMCE3, found in American and Dutch families, that results in a novel chromosomal breakage syndrome characterized by fatal pulmonary disease. Another focus is the development, execution and validation of a microscopy based synthetic sick/lethal screen using cells with knockdown of NSMCE4a. Studies of SMC5/6 in yeasts predict that compromising SMC5/6 function would lead to a dependence on other DNA
repair pathways. The results combined with patient data confirm that SMC5/6 is important in the absence of repair by non-homologous end joining and is particularly important under conditions of replication stress.

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry > QD0415 Biochemistry
Depositing User: Library Cataloguing
Date Deposited: 27 Apr 2017 08:37
Last Modified: 08 Jun 2018 09:32
URI: http://sro.sussex.ac.uk/id/eprint/67537

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