Abstract
DNA polymerase β (Pol β), a key enzyme in the DNA base excision repair (BER) pathway, is pivotal in maintaining the integrity and stability of genomes. One Pol β mutation that has been identified in tumors, R137Q (arginine to glutamine substitution), has been shown to lower polymerase activity, and impair its DNA repair capacity. However, the exact functional deficiency associated with this polymorphism in living organisms is still unknown. Here, we constructed Pol β R137Q knock-in mice, and found that homozygous knock-in mouse embryos were typically small in size and had a high mortality rate (21%). These embryonic abnormalities were caused by slow cell proliferation and increased apoptosis. In R137Q knock-in mouse embryos, the BER efficiency was severely impaired, which subsequently resulted in double-strand breaks (DSBs) and chromosomal aberrations. Furthermore, R137Q mouse embryo fibroblasts (MEFs) were more sensitive to DNA-damaging reagents, such as methyl methanesulfonate (MMS) and H2O2. They displayed a higher percentage of DSBs, and were more likely to undergo apoptosis. Our results indicate that R137 is a key amino acid site that is essential for proper Pol β functioning in maintaining genomic stability and embryo development.
Highlights
Important for the base excision repair (BER) process, as they can recruit downstream factors to the DNA repair site, reciprocally stimulate enzyme activities, and coordinate the highly ordered chemical reactions involved in BER
The knockout of Pol βin mice abolishes BER and causes the mutant cells to be hypersensitive to DNA damaging reagents, such as methyl methanesulfonate (MMS) and H2O2, which can result in early embryonic lethality
It has been reported that the Pol βR137Q variant has a significantly reduced polymerase activity and impaired BER efficiency, which subsequently contributes to genomic instability and the development of cancer[20]
Summary
Important for the BER process, as they can recruit downstream factors to the DNA repair site, reciprocally stimulate enzyme activities, and coordinate the highly ordered chemical reactions involved in BER. The knock-in of Pol βmutations in mice impairs BER, and causes low birth rates and abnormalities embryo development[27]. Findings from studies of mouse models with the Y265C Pol βvariant from the Sweasy laboratory indicate that Pol βmutations may impair BER and lead to developmental delays and autoimmune diseases[26,27]. It has been reported that the Pol βR137Q variant has a significantly reduced polymerase activity and impaired BER efficiency, which subsequently contributes to genomic instability and the development of cancer[20]. Our in vivo data show that the knock-in mouse embryos were small and had an increased mortality rate This suggests Pol βR137Q polymorphism may impair the BER efficiency, which might subsequently contribute to genomic instability and developmental abnormalities
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
