Recent advances in the study of immunodeficiency and DNA damage response

Morio, Tomohiro

doi:10.1007/s12185-017-2263-8

Cited by 19 publications

(11 citation statements)

References 54 publications

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“…In immunoglobulin class switch recombination, a DSB is induced by the activation of a cytidine deaminase before broken ends are repaired by NHEJ or MMR. Any deficiency in one of the effectors of these repair complexes impairs the generation of IgG diversity to fight foreign antigens (acquired immunity), and leads to immunodeficiency at various degrees or hyper-IgM syndrome [151].…”

Section: Immune Diseases and Inflammationmentioning

confidence: 99%

Proteins from the DNA Damage Response: Regulation, Dysfunction, and Anticancer Strategies

Molinaro

Martoriati

Cailliau

2021

Cancers

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Cells respond to genotoxic stress through a series of complex protein pathways called DNA damage response (DDR). These monitoring mechanisms ensure the maintenance and the transfer of a correct genome to daughter cells through a selection of DNA repair, cell cycle regulation, and programmed cell death processes. Canonical or non-canonical DDRs are highly organized and controlled to play crucial roles in genome stability and diversity. When altered or mutated, the proteins in these complex networks lead to many diseases that share common features, and to tumor formation. In recent years, technological advances have made it possible to benefit from the principles and mechanisms of DDR to target and eliminate cancer cells. These new types of treatments are adapted to the different types of tumor sensitivity and could benefit from a combination of therapies to ensure maximal efficiency.

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Section: Immune Diseases and Inflammationmentioning

confidence: 99%

Proteins from the DNA Damage Response: Regulation, Dysfunction, and Anticancer Strategies

Molinaro

Martoriati

Cailliau

2021

Cancers

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“…Researches showed that nuclear Hsp90 could bind to MRN complex and maintain its activity [ 39 , 40 ], others found that Hsp90 could interact with DDR proteins [ 26 ] and regulate the recruitment of 53BP1 to DSBs [ 41 ], suggesting Hsp90 may be related to DNA damage repair but the specific mechanism remains to be studied. Rad50 and Ku80 are key proteins for DSBs repair [ 42 ], which were downregulated after lamin-A further knockdown in our previous research [ 13 ]. Here, the effect of Hsp90 inhibition on DSBs repair was further studied.…”

Section: Discussionmentioning

confidence: 99%

Lamin-A interacting protein Hsp90 is required for DNA damage repair and chemoresistance of ovarian cancer cells

Wang

Chen

et al. 2021

Cell Death Dis

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Ovarian cancer is the most malignant gynecologic cancer. Previous studies found that lamin-A was associated with DNA damage repair proteins but the underlying mechanism remains unclear. We speculate that this may be related to its interacting proteins, such as Hsp90. The aim of this study is to investigate the effects of Hsp90 on DNA damage repair and chemoresistance of ovarian cancer cells. In our research, co-immunoprecipitation (co-IP) and mass spectrometry (MS) were used to identify proteins interacting with lamin-A and the interaction domain. Next, the relationship between lamin-A and Hsp90 was explored by Western blotting (WB) and immunofluorescence staining. Then, effect of Hsp90 inhibition on DNA damage repair was assessed through detecting Rad50 and Ku80 by WB. Furthermore, to test the roles of 17-AAG on cell chemosensitivity, CCK-8 and colony formation assay were carried out. Meanwhile, IC50 of cells were calculated, followed by immunofluorescence to detect DNA damage. At last, the mouse xenograft model was used in determining the capacity of 17-AAG and DDP to suppress tumor growth and metastatic potential. The results showed that lamin-A could interact with Hsp90 via the domain of lamin-A1-430. Besides, the distribution of Hsp90 could be affected by lamin-A. After lamin-A knockdown, Hsp90 decreased in the cytoplasm and increased in the nucleus, suggesting that the interaction between lamin-A and Hsp90 may be related to the nucleocytoplasmic transport of Hsp90. Moreover, inhibition of Hsp90 led to an obvious decrease in the expression of DSBs (DNA double-strand break) repair proteins, as well as cell proliferation ability upon DDP treatment and IC50 of DDP, causing more serious DNA damage. In addition, the combination of 17-AAG and DDP restrained the growth of ovarian cancer efficiently in vivo and prolonged the survival time of tumor-bearing mice.

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“…In contrast, the current study shows normal numbers of B and T cells in adult animals without BMT. More than a dozen molecules are involved in CSR ( 31 , 64 ), including those involved in the DNA damage response, components of the NHEJ pathway, and factors that induce topological changes in the nuclear architecture ( 48 ), and it is possible that Lsh promotes NHEJ activity by modulating known pathways. Interestingly, CSR of IgG2b was not significantly affected in Lsh-deficient B cells.…”

Section: Discussionmentioning

confidence: 99%

Lsh/HELLS is required for B lymphocyte development and immunoglobulin class switch recombination

Ren

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Mutation of HELLS (Helicase, Lymphoid-Specific)/Lsh in human DNA causes a severe immunodeficiency syndrome, but the nature of the defect remains unknown. We assessed here the role of Lsh in hematopoiesis using conditional Lsh knockout mice with expression of Mx1 or Vav Cre-recombinase. Bone marrow transplantation studies revealed that Lsh depletion in hematopoietic stem cells severely reduced B cell numbers and impaired B cell development in a hematopoietic cell-autonomous manner. Lsh-deficient mice without bone marrow transplantation exhibited lower Ig levels in vivo compared to controls despite normal peripheral B cell numbers. Purified B lymphocytes proliferated normally but produced less immunoglobulins in response to in vitro stimulation, indicating a reduced capacity to undergo class switch recombination (CSR). Analysis of germline transcripts, examination of double-stranded breaks using biotin-labeling DNA break assay, and End-seq analysis indicated that the initiation of the recombination process was unscathed. In contrast, digestion–circularization PCR analysis and high-throughput sequencing analyses of CSR junctions and a chromosomal break repair assay indicated an impaired ability of the canonical end-joining pathway in Lsh-deficient B cells. Our data suggest a hematopoietic cell-intrinsic role of Lsh in B cell development and in CSR providing a potential target for immunodeficiency therapy.

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Recent advances in the study of immunodeficiency and DNA damage response

Cited by 19 publications

References 54 publications

Proteins from the DNA Damage Response: Regulation, Dysfunction, and Anticancer Strategies

Proteins from the DNA Damage Response: Regulation, Dysfunction, and Anticancer Strategies

Lamin-A interacting protein Hsp90 is required for DNA damage repair and chemoresistance of ovarian cancer cells

Lsh/HELLS is required for B lymphocyte development and immunoglobulin class switch recombination

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