Investigating the DNA damage response in Streptomyces venezuelae

Stratton, Kathryn Jane (2023) Investigating the DNA damage response in Streptomyces venezuelae. Doctoral thesis, University of East Anglia.

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To cope with DNA damage stress, bacteria pause cell division whilst repairing DNA to maintain genomic integrity. A widely conserved response to DNA damage is the SOS response which relies on two proteins: RecA and LexA. Under normal conditions, LexA binds to a conserved motif in promoter regions, repressing transcription of its target genes. Following DNA damage, RecA inactivates the LexA repressor which results in the expression of genes involved in DNA damage repair. This response also triggers the production of specific cell division inhibitors resulting in temporary filamentous growth in unicellular bacteria. However, how naturally filamentous bacteria like Streptomyces cope with DNA damage is unknown.

To discover a DNA damage-induced checkpoint in Streptomyces, I first characterised the global SOS response of Streptomyces venezuelae. I performed ChIP-seq to identify the LexA regulon and RNA-seq to determine the associated transcriptomic changes in response to DNA damage. This led to the identification of dinK (division inhibitor K) which blocks sporulation when overexpressed. To better understand how DinK functions, I conducted a suppressor screen and identified SodK (suppressor of DinK), an uncharacterised protein with a predicted peptidoglycan binding domain, suggesting it could be involved in controlling cell wall remodelling or septum formation.

I explored the presence of SOS-independent responses to DNA damage in S. venezuelae. I demonstrated that ssgB is downregulated in an SOS-independent manner, contributing to the DNA damage-induced sporulation block. Additionally, I characterised the PafBC-mediated response, which was first identified in Mycobacterium. Together, this work has highlighted the complexity of the Streptomyces DNA damage response and opened up avenues for future research.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Biological Sciences
Depositing User: Chris White
Date Deposited: 11 Apr 2024 09:46
Last Modified: 11 Apr 2024 09:46

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