Mouse ZGRF1 helicase facilitates DNA repair and maintains efficient fertility
The recently characterised human ZGRF1 helicase promotes genomic stability by facilitating DNA interstrand crosslink repair. In its absence, human cells exhibit greater sensitivity towards anti-cancer drugs such as mitomycin C and camptothecin. Moreover, the downregulation of ZGRF1 expression is ass...
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| Language: | English |
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Elsevier
2025-01-01
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| Series: | Heliyon |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844025003597 |
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| author | Ernest Wee Kiat Lim Smaragda Kompocholi André Brannvoll K. Stine V. Bagge Jennifer R. Gruhn Javier Martin-Gonzalez Eliene Albers Ian D. Hickson Andrés López-Contreras Michael Lisby |
| author_facet | Ernest Wee Kiat Lim Smaragda Kompocholi André Brannvoll K. Stine V. Bagge Jennifer R. Gruhn Javier Martin-Gonzalez Eliene Albers Ian D. Hickson Andrés López-Contreras Michael Lisby |
| author_sort | Ernest Wee Kiat Lim |
| collection | DOAJ |
| description | The recently characterised human ZGRF1 helicase promotes genomic stability by facilitating DNA interstrand crosslink repair. In its absence, human cells exhibit greater sensitivity towards anti-cancer drugs such as mitomycin C and camptothecin. Moreover, the downregulation of ZGRF1 expression is associated with increased survival in cancer patients. These attributes point to ZGRF1 as a potential anti-cancer drug target. Here, we investigated the role of ZGRF1 in tumorigenesis using the mouse model. We generated a ZGRF1 mutant mouse and find that it is viable and displays normal development. However, at a cellular level, mouse embryonic fibroblasts exhibit sensitivity to ICLs and show elevated levels of the DNA damage marker γH2AX. In the absence of ZGRF1, the rates of tumorigenesis and tumour-free survival in Eμ-Myc and Trp53 knockout mice remained largely unaffected. These findings suggest a potential role for ZGRF1 in the proliferation of specific cancer types, highlighting avenues for further research in other cancer models. Additionally, beyond its known function in DNA repair, our study also reveals that ZGRF1 promotes meiotic recombination and that its loss results in reduced fertility in mice manifested as a 30 % reduction in meiotic crossovers and a 15 % reduction in litter size. |
| format | Article |
| id | doaj-art-d57655221c7b46ae8259907044fbefed |
| institution | Kabale University |
| issn | 2405-8440 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj-art-d57655221c7b46ae8259907044fbefed2025-02-02T05:28:42ZengElsevierHeliyon2405-84402025-01-01112e41979Mouse ZGRF1 helicase facilitates DNA repair and maintains efficient fertilityErnest Wee Kiat Lim0Smaragda Kompocholi1André Brannvoll2K. Stine V. Bagge3Jennifer R. Gruhn4Javier Martin-Gonzalez5Eliene Albers6Ian D. Hickson7Andrés López-Contreras8Michael Lisby9Section for Functional Genomics, Department of Biology University of Copenhagen, 2200, Copenhagen N, Denmark; Center for Chromosome Stability, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200, Copenhagen N, DenmarkSection for Functional Genomics, Department of Biology University of Copenhagen, 2200, Copenhagen N, DenmarkSection for Functional Genomics, Department of Biology University of Copenhagen, 2200, Copenhagen N, Denmark; Center for Chromosome Stability, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200, Copenhagen N, Denmark; Høiberg P/S, Adelgade 12, 1304, Copenhagen K, DenmarkSection for Functional Genomics, Department of Biology University of Copenhagen, 2200, Copenhagen N, Denmark; Emendo Research & Development, 2150, Nordhavn, DenmarkCenter for Chromosome Stability, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200, Copenhagen N, DenmarkCore Facility for Transgenic Mice, Department of Experimental Medicine, University of Copenhagen, 2200, Copenhagen N, DenmarkCenter for Chromosome Stability, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200, Copenhagen N, DenmarkCenter for Chromosome Stability, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200, Copenhagen N, DenmarkCenter for Chromosome Stability, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200, Copenhagen N, Denmark; Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Sevilla - Universidad Pablo de Olavide, Seville, SpainSection for Functional Genomics, Department of Biology University of Copenhagen, 2200, Copenhagen N, Denmark; Center for Chromosome Stability, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200, Copenhagen N, Denmark; Corresponding author. Section for Functional Genomics, Department of Biology University of Copenhagen, 2200, Copenhagen N, Denmark.The recently characterised human ZGRF1 helicase promotes genomic stability by facilitating DNA interstrand crosslink repair. In its absence, human cells exhibit greater sensitivity towards anti-cancer drugs such as mitomycin C and camptothecin. Moreover, the downregulation of ZGRF1 expression is associated with increased survival in cancer patients. These attributes point to ZGRF1 as a potential anti-cancer drug target. Here, we investigated the role of ZGRF1 in tumorigenesis using the mouse model. We generated a ZGRF1 mutant mouse and find that it is viable and displays normal development. However, at a cellular level, mouse embryonic fibroblasts exhibit sensitivity to ICLs and show elevated levels of the DNA damage marker γH2AX. In the absence of ZGRF1, the rates of tumorigenesis and tumour-free survival in Eμ-Myc and Trp53 knockout mice remained largely unaffected. These findings suggest a potential role for ZGRF1 in the proliferation of specific cancer types, highlighting avenues for further research in other cancer models. Additionally, beyond its known function in DNA repair, our study also reveals that ZGRF1 promotes meiotic recombination and that its loss results in reduced fertility in mice manifested as a 30 % reduction in meiotic crossovers and a 15 % reduction in litter size.http://www.sciencedirect.com/science/article/pii/S2405844025003597ZGRF1DNA helicaseInterstrand crosslinksDNA repairHomologous recombinationMouse model |
| spellingShingle | Ernest Wee Kiat Lim Smaragda Kompocholi André Brannvoll K. Stine V. Bagge Jennifer R. Gruhn Javier Martin-Gonzalez Eliene Albers Ian D. Hickson Andrés López-Contreras Michael Lisby Mouse ZGRF1 helicase facilitates DNA repair and maintains efficient fertility Heliyon ZGRF1 DNA helicase Interstrand crosslinks DNA repair Homologous recombination Mouse model |
| title | Mouse ZGRF1 helicase facilitates DNA repair and maintains efficient fertility |
| title_full | Mouse ZGRF1 helicase facilitates DNA repair and maintains efficient fertility |
| title_fullStr | Mouse ZGRF1 helicase facilitates DNA repair and maintains efficient fertility |
| title_full_unstemmed | Mouse ZGRF1 helicase facilitates DNA repair and maintains efficient fertility |
| title_short | Mouse ZGRF1 helicase facilitates DNA repair and maintains efficient fertility |
| title_sort | mouse zgrf1 helicase facilitates dna repair and maintains efficient fertility |
| topic | ZGRF1 DNA helicase Interstrand crosslinks DNA repair Homologous recombination Mouse model |
| url | http://www.sciencedirect.com/science/article/pii/S2405844025003597 |
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