المؤلفون: Filip Senigl, Yaakov Maman, Ravi K. Dinesh, Jukka Alinikula, Rashu B. Seth, Lubomira Pecnova, Arina D. Omer, Suhas S.P. Rao, David Weisz, Jean-Marie Buerstedde, Erez Lieberman Aiden, Rafael Casellas, Jiri Hejnar, David G. Schatz

المصدر: Cell Reports, Vol 29, Iss 12, Pp 3902-3915.e8 (2019)

مصطلحات موضوعية: Biology (General), QH301-705.5

الوصف: Summary: Somatic hypermutation (SHM) introduces point mutations into immunoglobulin (Ig) genes but also causes mutations in other parts of the genome. We have used lentiviral SHM reporter vectors to identify regions of the genome that are susceptible (“hot”) and resistant (“cold”) to SHM, revealing that SHM susceptibility and resistance are often properties of entire topologically associated domains (TADs). Comparison of hot and cold TADs reveals that while levels of transcription are equivalent, hot TADs are enriched for the cohesin loader NIPBL, super-enhancers, markers of paused/stalled RNA polymerase 2, and multiple important B cell transcription factors. We demonstrate that at least some hot TADs contain enhancers that possess SHM targeting activity and that insertion of a strong Ig SHM-targeting element into a cold TAD renders it hot. Our findings lead to a model for SHM susceptibility involving the cooperative action of cis-acting SHM targeting elements and the dynamic and architectural properties of TADs. : Senigl et al. show that genome susceptibility to somatic hypermutation (SHM) is confined within topologically associated domains (TADs) and is linked to markers of strong enhancers and stalled transcription and high levels of the cohesin loader NIPBL. Insertion of an ectopic SHM targeting element renders an entire TAD susceptible to SHM. Keywords: somatic hypermutation, activation induced deaminase, topologically associated domain, chromatin structure, chromatin loop extrusion, transcription factor

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2211124719315219Test; https://doaj.org/toc/2211-1247Test

الوصول الحر: https://doaj.org/article/2f5ff53bf6664a26b0aa7baa83fb62a9Test

المؤلفون: Jean-Marie Buerstedde, Noel Lowndes, David G Schatz

المصدر: eLife, Vol 3 (2014)

مصطلحات موضوعية: AID, homologous recombination, DNA repair, Medicine, Science, Biology (General), QH301-705.5

الوصف: The activation induced cytidine deaminase (AID) protein is known to initiate somatic hypermutation, gene conversion or switch recombination by cytidine deamination within the immunoglobulin loci. Using chromosomally integrated fluorescence reporter transgenes, we demonstrate a new recombinogenic activity of AID leading to intra- and intergenic deletions via homologous recombination of sequence repeats. Repeat recombination occurs at high frequencies even when the homologous sequences are hundreds of bases away from the positions of AID-mediated cytidine deamination, suggesting DNA end resection before strand invasion. Analysis of recombinants between homeologous repeats yielded evidence for heteroduplex formation and preferential migration of the Holliday junctions to the boundaries of sequence homology. These findings broaden the target and off-target mutagenic potential of AID and establish a novel system to study induced homologous recombination in vertebrate cells.

وصف الملف: electronic resource

العلاقة: https://elifesciences.org/articles/03110Test; https://doaj.org/toc/2050-084XTest

الوصول الحر: https://doaj.org/article/b98dd0701533462b8301536e36ba1e92Test

المؤلفون: Jean-Marie Buerstedde, Jukka Alinikula, Hiroshi Arakawa, Jessica J McDonald, David G Schatz

المصدر: PLoS Biology, Vol 12, Iss 4, p e1001831 (2014)

مصطلحات موضوعية: Biology (General), QH301-705.5

الوصف: Somatic hypermutation (SH) generates point mutations within rearranged immunoglobulin (Ig) genes of activated B cells, providing genetic diversity for the affinity maturation of antibodies. SH requires the activation-induced cytidine deaminase (AID) protein and transcription of the mutation target sequence, but how the Ig gene specificity of mutations is achieved has remained elusive. We show here using a sensitive and carefully controlled assay that the Ig enhancers strongly activate SH in neighboring genes even though their stimulation of transcription is negligible. Mutations in certain E-box, NFκB, MEF2, or Ets family binding sites--known to be important for the transcriptional role of Ig enhancers--impair or abolish the activity. Full activation of SH typically requires a combination of multiple Ig enhancer and enhancer-like elements. The mechanism is evolutionarily conserved, as mammalian Ig lambda and Ig heavy chain intron enhancers efficiently stimulate hypermutation in chicken cells. Our results demonstrate a novel regulatory function for Ig enhancers, indicating that they either recruit AID or alter the accessibility of the nearby transcription units.

وصف الملف: electronic resource

العلاقة: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24691034/?tool=EBITest; https://doaj.org/toc/1544-9173Test; https://doaj.org/toc/1545-7885Test

الوصول الحر: https://doaj.org/article/d8c75f8713464da9bd7f8ad340ca1263Test

المؤلفون: Artem Blagodatski, Vera Batrak, Sabine Schmidl, Ulrike Schoetz, Randolph B Caldwell, Hiroshi Arakawa, Jean-Marie Buerstedde

المصدر: PLoS Genetics, Vol 5, Iss 1, p e1000332 (2009)

مصطلحات موضوعية: Genetics, QH426-470

الوصف: Hypermutation of the immunoglobulin (Ig) genes requires Activation Induced cytidine Deaminase (AID) and transcription, but it remains unclear why other transcribed genes of B cells do not mutate. We describe a reporter transgene crippled by hypermutation when inserted into or near the Ig light chain (IgL) locus of the DT40 B cell line yet stably expressed when inserted into other chromosomal positions. Step-wise deletions of the IgL locus revealed that a sequence extending for 9.8 kilobases downstream of the IgL transcription start site confers the hypermutation activity. This sequence, named DIVAC for diversification activator, efficiently activates hypermutation when inserted at non-Ig loci. The results significantly extend previously reported findings on AID-mediated gene diversification. They show by both deletion and insertion analyses that cis-acting sequences predispose neighboring transcription units to hypermutation.

وصف الملف: electronic resource

العلاقة: http://europepmc.org/articles/PMC2607555?pdf=renderTest; https://doaj.org/toc/1553-7390Test; https://doaj.org/toc/1553-7404Test

الوصول الحر: https://doaj.org/article/079156d0041a4c42acafaec995b75adaTest

المؤلفون: Hiroshi Arakawa, George-Lucian Moldovan, Huseyin Saribasak, Nesibe Nur Saribasak, Stefan Jentsch, Jean-Marie Buerstedde

المصدر: PLoS Biology, Vol 4, Iss 11, p e366 (2006)

مصطلحات موضوعية: Biology (General), QH301-705.5

الوصف: Proliferating cell nuclear antigen (PCNA) is a DNA polymerase cofactor and regulator of replication-linked functions. Upon DNA damage, yeast and vertebrate PCNA is modified at the conserved lysine K164 by ubiquitin, which mediates error-prone replication across lesions via translesion polymerases. We investigated the role of PCNA ubiquitination in variants of the DT40 B cell line that are mutant in K164 of PCNA or in Rad18, which is involved in PCNA ubiquitination. Remarkably, the PCNA(K164R) mutation not only renders cells sensitive to DNA-damaging agents, but also strongly reduces activation induced deaminase-dependent single-nucleotide substitutions in the immunoglobulin light-chain locus. This is the first evidence, to our knowledge, that vertebrates exploit the PCNA-ubiquitin pathway for immunoglobulin hypermutation, most likely through the recruitment of error-prone DNA polymerases.

وصف الملف: electronic resource

العلاقة: http://europepmc.org/articles/PMC1618868?pdf=renderTest; https://doaj.org/toc/1544-9173Test; https://doaj.org/toc/1545-7885Test

الوصول الحر: https://doaj.org/article/06721dd8b6824b728333a91a571b999aTest

المؤلفون: Hiroshi Arakawa, Huseyin Saribasak, Jean-Marie Buerstedde

المصدر: PLoS Biology, Vol 2, Iss 7, p E179 (2004)

مصطلحات موضوعية: Biology (General), QH301-705.5

الوصف: Depending on the species and the lymphoid organ, activation-induced cytidine deaminase (AID) expression triggers diversification of the rearranged immunoglobulin (Ig) genes by pseudo V (psiV) gene- templated gene conversion or somatic hypermutation. To investigate how AID can alternatively induce recombination or hypermutation, psiV gene deletions were introduced into the rearranged light chain locus of the DT40 B-cell line. We show that the stepwise removal of the psiV donors not only reduces and eventually abolishes Ig gene conversion, but also activates AID-dependent Ig hypermutation. This strongly supports a model in which AID induces a common modification in the rearranged V(D)J segment, leading to a conversion tract in the presence of nearby donor sequences and to a point mutation in their absence.

وصف الملف: electronic resource

العلاقة: http://europepmc.org/articles/PMC449846?pdf=renderTest; https://doaj.org/toc/1544-9173Test; https://doaj.org/toc/1545-7885Test

الوصول الحر: https://doaj.org/article/3b7e841a4700475cb4a4761554aa5200Test

المؤلفون: Jun Nakamura, James A. Swenberg, Masami Watanabe, Shunichi Takeda, Minoru Takata, Douglas K. Bishop, Mitsuyoshi Yamazoe, Julian E. Sale, David A.F. Gillespie, Jean-Marie Buerstedde, Hiroshi Arakawa, Eiichiro Sonoda, April M. Luke, Keizo Tano, Ayumi Nakamura, John R. Ridpath

الوصف: Formaldehyde is an aliphatic monoaldehyde and is a highly reactive environmental human carcinogen. Whereas humans are continuously exposed to exogenous formaldehyde, this reactive aldehyde is a naturally occurring biological compound that is present in human plasma at concentrations ranging from 13 to 97 μmol/L. It has been well documented that DNA-protein crosslinks (DPC) likely play an important role with regard to the genotoxicity and carcinogenicity of formaldehyde. However, little is known about which DNA damage response pathways are essential for cells to counteract formaldehyde. In the present study, we first assessed the DNA damage response to plasma levels of formaldehyde using chicken DT40 cells with targeted mutations in various DNA repair genes. Here, we show that the hypersensitivity to formaldehyde is detected in DT40 mutants deficient in the BRCA/FANC pathway, homologous recombination, or translesion DNA synthesis. In addition, FANCD2-deficient DT40 cells are hypersensitive to acetaldehyde, but not to acrolein, crotonaldehyde, glyoxal, and methylglyoxal. Human cells deficient in FANCC and FANCG are also hypersensitive to plasma levels of formaldehyde. These results indicate that the BRCA/FANC pathway is essential to counteract DPCs caused by aliphatic monoaldehydes. Based on the results obtained in the present study, we are currently proposing that endogenous formaldehyde might have an effect on highly proliferating cells, such as bone marrow cells, as well as an etiology of cancer in Fanconi anemia patients. [Cancer Res 2007;67(23):11117–22]

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::133d5ae3c34c1b87681a5e0bbb705420Test
https://doi.org/10.1158/0008-5472.c.6496742Test

المؤلفون: Jun Nakamura, James A. Swenberg, Masami Watanabe, Shunichi Takeda, Minoru Takata, Douglas K. Bishop, Mitsuyoshi Yamazoe, Julian E. Sale, David A.F. Gillespie, Jean-Marie Buerstedde, Hiroshi Arakawa, Eiichiro Sonoda, April M. Luke, Keizo Tano, Ayumi Nakamura, John R. Ridpath

الوصف: Supplementary Figure 1 from Cells Deficient in the FANC/BRCA Pathway Are Hypersensitive to Plasma Levels of Formaldehyde

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4b1095106e3b03f58cc9dcda62c8d998Test
https://doi.org/10.1158/0008-5472.22371317Test

المؤلفون: Eiichiro Sonoda, Shunichi Takeda, Nobuo Hashimoto, Jun A. Takahashi, Kasumi Araki, Takuo Kawamoto, Mitsuyoshi Yamazoe, Jean-Marie Buerstedde, Hiroshi Arakawa, Minoru Takata, Kazuhiko Yamamoto, Masamichi Ishiai, Mioko Ohzeki, Seiki Hirano, Douglas K. Bishop, Brian J. Orelli, Michio Yoshimura, Koji Kikuchi, Toru Fukushima, Alihossein Saberi, Helfrid Hochegger, Kuniharu Nojima

الوصف: Supplementary Data from Multiple Repair Pathways Mediate Tolerance to Chemotherapeutic Cross-linking Agents in Vertebrate Cells

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ae7a65a64915b1ca91fa4754a41b7dcdTest
https://doi.org/10.1158/0008-5472.22364519.v1Test

المؤلفون: Eiichiro Sonoda, Shunichi Takeda, Nobuo Hashimoto, Jun A. Takahashi, Kasumi Araki, Takuo Kawamoto, Mitsuyoshi Yamazoe, Jean-Marie Buerstedde, Hiroshi Arakawa, Minoru Takata, Kazuhiko Yamamoto, Masamichi Ishiai, Mioko Ohzeki, Seiki Hirano, Douglas K. Bishop, Brian J. Orelli, Michio Yoshimura, Koji Kikuchi, Toru Fukushima, Alihossein Saberi, Helfrid Hochegger, Kuniharu Nojima

الوصف: Cross-linking agents that induce DNA interstrand cross-links (ICL) are widely used in anticancer chemotherapy. Yeast genetic studies show that nucleotide excision repair (NER), Rad6/Rad18-dependent postreplication repair, homologous recombination, and cell cycle checkpoint pathway are involved in ICL repair. To study the contribution of DNA damage response pathways in tolerance to cross-linking agents in vertebrates, we made a panel of gene-disrupted clones from chicken DT40 cells, each defective in a particular DNA repair or checkpoint pathway, and measured the sensitivities to cross-linking agents, including cis-diamminedichloroplatinum (II) (cisplatin), mitomycin C, and melphalan. We found that cells harboring defects in translesion DNA synthesis (TLS), Fanconi anemia complementation groups (FANC), or homologous recombination displayed marked hypersensitivity to all the cross-linking agents, whereas NER seemed to play only a minor role. This effect of replication-dependent repair pathways is distinctively different from the situation in yeast, where NER seems to play a major role in dealing with ICL. Cells deficient in Rev3, the catalytic subunit of TLS polymerase Polζ, showed the highest sensitivity to cisplatin followed by fanc-c. Furthermore, epistasis analysis revealed that these two mutants work in the same pathway. Our genetic comprehensive study reveals a critical role for DNA repair pathways that release DNA replication block at ICLs in cellular tolerance to cross-linking agents and could be directly exploited in designing an effective chemotherapy. (Cancer Res 2005; 65(24): 11704-11)

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a98e2678c40af7f2f7d7b74a22fe4820Test
https://doi.org/10.1158/0008-5472.c.6494222Test