DNA damage responses in murine Pre-B cells with genetic deficiencies in damage response genes

Innes, Cynthia L.; Hesse, Jill E.; Morales, Abigail J; Helmink, Beth A.; Schurman, Shepherd H.; Sleckman, Barry P.; Paules, Richard S.

doi:10.1080/15384101.2019.1693118

Cited by 7 publications

(9 citation statements)

References 68 publications

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“…234 . It has been confirmed that DNA-PKcs can identify DSBs post-IR insult and facilitate "messy" broken end processing and DNA ligation by recruiting the proteins responsible for DNA damage repair processing and ultimately ligating the broken DNA ends 235,236 . DNA-PKcs was first discovered due to the observation that dsDNA can modulate the phosphorylation of a series of proteins 237 .…”

Section: Targeting Dna Damage Repair To Sensitize Cancer Cells To Radiationmentioning

confidence: 99%

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

Huang

Zhou

2020

Sig Transduct Target Ther

603

457

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Radiotherapy is one of the most common countermeasures for treating a wide range of tumors. However, the radioresistance of cancer cells is still a major limitation for radiotherapy applications. Efforts are continuously ongoing to explore sensitizing targets and develop radiosensitizers for improving the outcomes of radiotherapy. DNA double-strand breaks are the most lethal lesions induced by ionizing radiation and can trigger a series of cellular DNA damage responses (DDRs), including those helping cells recover from radiation injuries, such as the activation of DNA damage sensing and early transduction pathways, cell cycle arrest, and DNA repair. Obviously, these protective DDRs confer tumor radioresistance. Targeting DDR signaling pathways has become an attractive strategy for overcoming tumor radioresistance, and some important advances and breakthroughs have already been achieved in recent years. On the basis of comprehensively reviewing the DDR signal pathways, we provide an update on the novel and promising druggable targets emerging from DDR pathways that can be exploited for radiosensitization. We further discuss recent advances identified from preclinical studies, current clinical trials, and clinical application of chemical inhibitors targeting key DDR proteins, including DNA-PKcs (DNA-dependent protein kinase, catalytic subunit), ATM/ATR (ataxia-telangiectasia mutated and Rad3-related), the MRN (MRE11-RAD50-NBS1) complex, the PARP (poly[ADP-ribose] polymerase) family, MDC1, Wee1, LIG4 (ligase IV), CDK1, BRCA1 (BRCA1 C terminal), CHK1, and HIF-1 (hypoxia-inducible factor-1). Challenges for ionizing radiation-induced signal transduction and targeted therapy are also discussed based on recent achievements in the biological field of radiotherapy.

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Section: Targeting Dna Damage Repair To Sensitize Cancer Cells To Radiationmentioning

confidence: 99%

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

Huang

Zhou

2020

Sig Transduct Target Ther

603

457

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“…In particular, the role of MDC1 during the V(D)J recombination might be to stabilize the DNA repair complex, to protect the free DNA ends, to ensure efficient recruitment of downstream DDR factors, such as 53BP1, PTIP, RIF1, Shieldin, etc. [1,[42][43][44]47,55,58], or to exit from the G1 phase of the cell cycle following the RAG-induced DSB [59]. Further research is required to identify specific roles of MDC1 and XLF in DNA repair.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the lack of MDC1 alone resulted in significantly reduced proliferation rates of human HAP1 cells at 96 and 120 h (Figure 1). These observations may suggest that, first, the lack of MDC1 is compensated by the presence of XLF in murine cells, and second, that the MDC1 is required for efficient DNA repair and proliferation of human cells, likely by supporting the cell cycle progression and DNA damage tolerance [47,59].…”

Section: Double Knockoutsmentioning

confidence: 99%

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

et al. 2019

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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.

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“…In particular, the role of MDC1 during the V(D)J recombination might be to stabilize the DNA repair complex, to protect the free DNA ends, or to ensure efficient recruitment of downstream DDR factors, such as 53BP1, PTIP, RIF1, Shieldin, etc. [1,[42][43][44]47,55,58], or exit from the G1 phase of the cell cycle following the RAG-induced DSB [59]. Further research is required to identify specific roles of MDC1 and XLF in DNA repair.…”

Section: Discussionmentioning

confidence: 99%

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

Beck

Castañeda‐Zegarra

Huse

et al. 2019

Preprint

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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.

show abstract

DNA damage responses in murine Pre-B cells with genetic deficiencies in damage response genes

Cited by 7 publications

References 68 publications

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

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

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

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