Identification of histone demethylase UTX-1 as a new regulator of P53 dependent apoptosis in C. elegans germline

Abstract

Our genome is exposed to various endogenous and exogenous damaging agents that compromise its integrity. As such, a complex network of genes referred to as the DNA damage response (DDR) is activated in response to DNA damage to help preserve the genomic integrity and its accurate transmission to the next generation. In this study, we aimed to identify novel proteins involved in the maintenance of genomic stability by performing a reverse genetic screening and hypersensitivity assay and uncover the mechanism behind how one of the candidates identified from our genetic screen contribute to genomic stability. By screening 252 gene clones from the chromatin-associated subset of the Ahringer RNAi library, we identified 25 candidate genes that showed increased hypersensitivity to the chemotherapeutic drug, hydroxyurea, upon their depletion. Of those 25 candidates, we selected utx-1 gene for further characterization and found that depletion of utx-1 significantly upregulated apoptosis in the germline of adult hermaphrodites, in a cep-1(p53)-dependent manner but had little to no effect on DNA damage signaling reported by a lack of CHK-1 activation and only a subtle increase in RPA-1 foci formation. Thus, our results provide further insight to the previously ambiguous reported role of UTX in DDR and apoptosis as well as its potential role as a therapeutic target in cancer treatment.

Date of Award	2023
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences