Characterisation of BOD1L, a novel player in the DNA damage response

Mottram, Rachel Maria Antonia (2020). Characterisation of BOD1L, a novel player in the DNA damage response. University of Birmingham. Ph.D.

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Abstract

Many components of the DNA damage response are known to function across multiple pathways. Bi-orientation defect 1-like (BOD1L) was recently identified as a modulator of nucleolytic resection of stalled replication forks. However, its potential roles in the resolution of other types of DNA damage were unexplored.

My thesis demonstrates that BOD1L interacts with the 53BP1 effector RIF1. This interaction is critical for the recruitment of RIF1 to DNA double-strand breaks (DSBs) induced by ionising radiation (IR). Collectively, these proteins antagonise the inappropriate accumulation of BRCA1 at these breaks, thereby suppressing CtIP- and MRE11-dependent resection. In the absence of BOD1L, aberrant resection ultimately compromises genome stability and cell survival. Homologous recombination is unaffected by the depletion of BOD1L; however, this factor is required for the 53BP1-dependent process of non-homologous end joining. Furthermore, BOD1L and RIF1 also modulate resection of Camptothecin (CPT)-induced DSBs.

In summary, I have demonstrated a novel interaction between BOD1L and RIF1, which is fundamental to its control of DSB resection following exposure to IR or CPT. Therefore, alongside its function during replication stress, BOD1L preserves genome stability by influencing DSB repair pathway choice, ensuring appropriate resolution of DSBs inflicted by a variety of genotoxins.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):