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Xinran Huang

DPhil Student

Investigating the function of p53 in hematopoietic stem cells under normal and stress conditions

p53 is a central tumour suppressor that safeguards genome stability and responses to various types of stress. In particular, a p53 response is activated in hematopoietic stem cells (HSCs) upon both endogenous and exogenous sources of DNA damage.

The roles of p53 in HSCs remain poorly understood. While endogenous aldehyde stress caused HSC attrition, p53 deletion rescued both the number and function of HSCs without introducing further genomic instability (Garraycochea et al. 2018). Similar findings were reported in the case of exogenous DNA damage (Bondar and Medzhitov 2010; Marysyk et al. 2010) where p53 deficiency in HSCs provided a selective advantage upon irradiation. These data indicated that p53 does not act as a “guardian of the genome” in the HSC compartment, but instead as a “quality control” mechanism that eliminates any damaged HSCs.

On the other hand, p53 deficiency did not confer a growth advantage in vivo under normal conditions (Bondar and Medzhitov 2010), which suggested that they are in a distinct status even in the absence of stress. Damaged cells that escape p53 surveillance may be dependent on this unique status. Therefore, understanding this p53-deficient state in HSCs could unveil potential therapeutic vulnerabilities.

My project aims to delineate the p53 response in HSCs and characterise the p53-deficient state of HSCs under physiological and stress conditions. I will be use transgenic animal models and ex vivo culture of HSCs to study the function of p53 in the hematopoietic system.