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Generation of a Mouse Model Lacking the Non-Homologous End-Joining Factor Mri/Cyren
Open AccessArticle

Mediator of DNA Damage Checkpoint Protein 1 Facilitates V(D)J Recombination in Cells Lacking DNA Repair Factor XLF

1
Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway
2
St. Olavs Hospital, Trondheim University Hospital, Clinic of Medicine, Postboks 3250 Sluppen, 7006 Trondheim, Norway
3
Department of Biosciences and Nutrition (BioNuT), Karolinska Institutet, 14183 Huddinge, Sweden
*
Author to whom correspondence should be addressed.
Biomolecules 2020, 10(1), 60; https://doi.org/10.3390/biom10010060
Received: 27 November 2019 / Revised: 23 December 2019 / Accepted: 24 December 2019 / Published: 30 December 2019
(This article belongs to the Special Issue DNA Damage Response)
DNA double-strand breaks (DSBs) trigger the Ataxia telangiectasia mutated (ATM)-dependent DNA damage response (DDR), which consists of histone H2AX, MDC1, RNF168, 53BP1, PTIP, RIF1, Rev7, and Shieldin. Early stages of B and T lymphocyte development are dependent on recombination activating gene (RAG)-induced DSBs that form the basis for further V(D)J recombination. Non-homologous end joining (NHEJ) pathway factors recognize, process, and ligate DSBs. Based on numerous loss-of-function studies, DDR factors were thought to be dispensable for the V(D)J recombination. In particular, mice lacking Mediator of DNA Damage Checkpoint Protein 1 (MDC1) possessed nearly wild-type levels of mature B and T lymphocytes in the spleen, thymus, and bone marrow. NHEJ factor XRCC4-like factor (XLF)/Cernunnos is functionally redundant with ATM, histone H2AX, and p53-binding protein 1 (53BP1) during the lymphocyte development in mice. Here, we genetically inactivated MDC1, XLF, or both MDC1 and XLF in murine vAbl pro-B cell lines and, using chromosomally integrated substrates, demonstrated that MDC1 stimulates the V(D)J recombination in cells lacking XLF. Moreover, combined inactivation of MDC1 and XLF in mice resulted in synthetic lethality. Together, these findings suggest that MDC1 and XLF are functionally redundant during the mouse development, in general, and the V(D)J recombination, in particular. View Full-Text
Keywords: V(D)J recombination; vAbl cells; B lymphocytes; mouse genetics; genetic interaction V(D)J recombination; vAbl cells; B lymphocytes; mouse genetics; genetic interaction
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Beck, C.; Castañeda-Zegarra, S.; Huse, C.; Xing, M.; Oksenych, V. Mediator of DNA Damage Checkpoint Protein 1 Facilitates V(D)J Recombination in Cells Lacking DNA Repair Factor XLF. Biomolecules 2020, 10, 60.

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