TY - BOOK

T1 - Characterising the Organismal Role of ZGRF1 in Mus Musculus

AU - Lim, Ernest Wee Kiat

PY - 2024

Y1 - 2024

N2 - Conventional anti-cancer therapies rely on agents that induce DNA lesions in the genome to compromise the survival of cancer cells. However, in certain cancers where repair pathways remain functional, DNA lesions are repaired, diminishing the effectiveness of the treatment. The impairment of DNA repair pathways using small molecule inhibitors in combination with traditional DNA-damaging agents has been shown to enhance the efficacy of DNA-damaging agents in newer treatment strategies. Hence, through the identification of new drug targets within the DNA damage response, novel therapeutic potentials can be uncovered.The recently characterised ZGRF1 helicase was shown to facilitate DNA interstrand crosslink (ICL) repair, promoting genomic stability. In its absence, cells exhibit increased sensitivities to clinical anti-cancer drugs such as mitomycin C and camptothecin. Besides, low expression of ZGRF1 was shown to improve the prognosis of several cancer types, designating it as a potential cooperative drug target for cancer therapies. To investigate the role of ZGRF1 in the maintenance of genome stability and ICL repair at the organismal level, mice lacking ZGRF1 were generated. To assess the impact of ZGRF1 on tumorigenesis, Zgrf1 knockout (KO) mice were cross-bred with the Eμ-Myc and Trp53 cancer models, and the resulting progenies were observed for survival. In addition, Zgrf1 KO mice were cross-bred with Adh5 mice to examine if the accumulation of endogenous formaldehyde could induce severe phenotypic or developmental abnormalities. Given that Zgrf1 is demonstrated to promote crossover formation, and that its yeast homolog Dbl2 is associated with meiosis, the fertility of Zgrf1 KO mice was also examined.Through these studies, ZGRF1 was shown to play a role in ICL repair. In its absence, mice were able to develop normally, even in the condition of increased levels of endogenous formaldehyde. While ZGRF1 does not affect the rate of tumorigenesis in Eμ-Myc and Trp53 cancer models, its absence was found to improve the survivability of Trp53 heterozygous mice, possibly by limiting gene conversion events and the resulting loss of heterozygosity. ZGRF1 was also implicated in fertility, facilitating crossover formation during meiosis. Taken together, our data show that ZGRF1 is involved in the generation of crossovers, underscoring its pivotal role in the repair of double-strand breaks during mitosis and meiosis.

AB - Conventional anti-cancer therapies rely on agents that induce DNA lesions in the genome to compromise the survival of cancer cells. However, in certain cancers where repair pathways remain functional, DNA lesions are repaired, diminishing the effectiveness of the treatment. The impairment of DNA repair pathways using small molecule inhibitors in combination with traditional DNA-damaging agents has been shown to enhance the efficacy of DNA-damaging agents in newer treatment strategies. Hence, through the identification of new drug targets within the DNA damage response, novel therapeutic potentials can be uncovered.The recently characterised ZGRF1 helicase was shown to facilitate DNA interstrand crosslink (ICL) repair, promoting genomic stability. In its absence, cells exhibit increased sensitivities to clinical anti-cancer drugs such as mitomycin C and camptothecin. Besides, low expression of ZGRF1 was shown to improve the prognosis of several cancer types, designating it as a potential cooperative drug target for cancer therapies. To investigate the role of ZGRF1 in the maintenance of genome stability and ICL repair at the organismal level, mice lacking ZGRF1 were generated. To assess the impact of ZGRF1 on tumorigenesis, Zgrf1 knockout (KO) mice were cross-bred with the Eμ-Myc and Trp53 cancer models, and the resulting progenies were observed for survival. In addition, Zgrf1 KO mice were cross-bred with Adh5 mice to examine if the accumulation of endogenous formaldehyde could induce severe phenotypic or developmental abnormalities. Given that Zgrf1 is demonstrated to promote crossover formation, and that its yeast homolog Dbl2 is associated with meiosis, the fertility of Zgrf1 KO mice was also examined.Through these studies, ZGRF1 was shown to play a role in ICL repair. In its absence, mice were able to develop normally, even in the condition of increased levels of endogenous formaldehyde. While ZGRF1 does not affect the rate of tumorigenesis in Eμ-Myc and Trp53 cancer models, its absence was found to improve the survivability of Trp53 heterozygous mice, possibly by limiting gene conversion events and the resulting loss of heterozygosity. ZGRF1 was also implicated in fertility, facilitating crossover formation during meiosis. Taken together, our data show that ZGRF1 is involved in the generation of crossovers, underscoring its pivotal role in the repair of double-strand breaks during mitosis and meiosis.

M3 - Ph.D. thesis

BT - Characterising the Organismal Role of ZGRF1 in Mus Musculus

PB - Department of Biology, Faculty of Science, University of Copenhagen

ER -