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Article: Metastasis of colon cancer requires Dickkopf-2 to generate cancer cells with Paneth cell properties.

Shin, Jae Hun / Park, Jooyoung / Lim, Jaechul / Jeong, Jaekwang / Dinesh, Ravi K / Maher, Stephen E / Hong, Jun Young / Wysolmerski, John / Choi, Jungmin / Bothwell, Alfred L M

bioRxiv : the preprint server for biology

2024

Abstract: Metastasis is the leading cause of cancer-related mortality. Paneth cells provide stem cell niche factors in homeostatic conditions, but the underlying mechanisms of cancer stem cell niche development are unclear. Here we report that Dickkopf-2 (DKK2) is ...

Abstract	Metastasis is the leading cause of cancer-related mortality. Paneth cells provide stem cell niche factors in homeostatic conditions, but the underlying mechanisms of cancer stem cell niche development are unclear. Here we report that Dickkopf-2 (DKK2) is essential for the generation of cancer cells with Paneth cell properties during colon cancer metastasis. Splenic injection of
Language	English
Publishing date	2024-04-15
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.12.589235
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Article ; Online: HMCES protects immunoglobulin genes specifically from deletions during somatic hypermutation.

Wu, Lizhen / Shukla, Vipul / Yadavalli, Anurupa Devi / Dinesh, Ravi K / Xu, Dijin / Rao, Anjana / Schatz, David G

Genes & development

2022 Volume 36, Issue 7-8, Page(s) 433–450

Abstract: Somatic hypermutation (SHM) produces point mutations in immunoglobulin (Ig) genes in B cells when uracils created by the activation-induced deaminase are processed in a mutagenic manner by enzymes of the base excision repair (BER) and mismatch repair ( ... ...

Abstract	Somatic hypermutation (SHM) produces point mutations in immunoglobulin (Ig) genes in B cells when uracils created by the activation-induced deaminase are processed in a mutagenic manner by enzymes of the base excision repair (BER) and mismatch repair (MMR) pathways. Such uracil processing creates DNA strand breaks and is susceptible to the generation of deleterious deletions. Here, we demonstrate that the DNA repair factor HMCES strongly suppresses deletions without significantly affecting other parameters of SHM in mouse and human B cells, thereby facilitating the production of antigen-specific antibodies. The deletion-prone repair pathway suppressed by HMCES operates downstream from the uracil glycosylase UNG and is mediated by the combined action of BER factor APE2 and MMR factors MSH2, MSH6, and EXO1. HMCES's ability to shield against deletions during SHM requires its capacity to form covalent cross-links with abasic sites, in sharp contrast to its DNA end-joining role in class switch recombination but analogous to its genome-stabilizing role during DNA replication. Our findings lead to a novel model for the protection of Ig gene integrity during SHM in which abasic site cross-linking by HMCES intercedes at a critical juncture during processing of vulnerable gapped DNA intermediates by BER and MMR enzymes.
MeSH term(s)	Animals ; Cytidine Deaminase/genetics ; Cytidine Deaminase/metabolism ; DNA/genetics ; DNA-Binding Proteins ; Genes, Immunoglobulin/genetics ; Immunoglobulin Class Switching/genetics ; Mice ; Somatic Hypermutation, Immunoglobulin/genetics ; Uracil
Chemical Substances	DNA-Binding Proteins ; Hmces protein, mouse ; Uracil (56HH86ZVCT) ; DNA (9007-49-2) ; Cytidine Deaminase (EC 3.5.4.5)
Language	English
Publishing date	2022-04-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	806684-x
ISSN	1549-5477 ; 0890-9369
ISSN (online)	1549-5477
ISSN	0890-9369
DOI	10.1101/gad.349438.122
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Zs.MG 54: Show issues

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Article ; Online: PD-1, gender, and autoimmunity.

Dinesh, Ravi K / Hahn, Bevra H / Singh, Ram Pyare

Autoimmunity reviews

2010 Volume 9, Issue 8, Page(s) 583–587

Abstract: Programmed death 1 (PD-1) and its ligands (PD-L1 and PD-L2) are responsible for inhibitory T cell signaling that helps mediate the mechanisms of tolerance and immune homeostasis. The PD-1:PD-L signaling pathway has been shown to play an important role in ...

Abstract	Programmed death 1 (PD-1) and its ligands (PD-L1 and PD-L2) are responsible for inhibitory T cell signaling that helps mediate the mechanisms of tolerance and immune homeostasis. The PD-1:PD-L signaling pathway has been shown to play an important role in a variety of diseases, including autoimmune conditions, chronic infection, and cancer. Recently, investigators have explored the role of sex hormones in modulating the pathway in autoimmune conditions. Exploring the effects of sex hormones on the PD-1:PD-L pathway could shed light on the gender biased nature of many autoimmune conditions as well as aide in the development of therapeutics targeting the immune system.
MeSH term(s)	Animals ; Antigens, CD/immunology ; Apoptosis Regulatory Proteins/immunology ; Autoimmunity/immunology ; B7-H1 Antigen ; Female ; Gonadal Steroid Hormones/immunology ; Humans ; Immune Tolerance/immunology ; Intercellular Signaling Peptides and Proteins/immunology ; Male ; Programmed Cell Death 1 Ligand 2 Protein ; Programmed Cell Death 1 Receptor ; Sex Characteristics ; Signal Transduction/immunology ; T-Lymphocytes/immunology
Chemical Substances	Antigens, CD ; Apoptosis Regulatory Proteins ; B7-H1 Antigen ; CD274 protein, human ; Gonadal Steroid Hormones ; Intercellular Signaling Peptides and Proteins ; PDCD1 protein, human ; PDCD1LG2 protein, human ; Programmed Cell Death 1 Ligand 2 Protein ; Programmed Cell Death 1 Receptor
Language	English
Publishing date	2010-04-28
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2144145-5
ISSN	1873-0183 ; 1568-9972
ISSN (online)	1873-0183
ISSN	1568-9972
DOI	10.1016/j.autrev.2010.04.003
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Article ; Online: Topologically Associated Domains Delineate Susceptibility to Somatic Hypermutation.

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

Cell reports

2019 Volume 29, Issue 12, Page(s) 3902–3915.e8

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Cell Line, Tumor ; Cytidine Deaminase/genetics ; Cytidine Deaminase/metabolism ; Enhancer Elements, Genetic/genetics ; HEK293 Cells ; Humans ; Lentivirus ; Male ; Mutation/genetics ; Plasmids/genetics ; RNA Polymerase II/genetics ; RNA Polymerase II/metabolism ; Somatic Hypermutation, Immunoglobulin/genetics
Chemical Substances	RNA Polymerase II (EC 2.7.7.-) ; Cytidine Deaminase (EC 3.5.4.5)
Language	English
Publishing date	2019-12-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2019.11.039
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Article ; Online: Transcription factor binding at Ig enhancers is linked to somatic hypermutation targeting.

Dinesh, Ravi K / Barnhill, Benjamin / Ilanges, Anoj / Wu, Lizhen / Michelson, Daniel A / Senigl, Filip / Alinikula, Jukka / Shabanowitz, Jeffrey / Hunt, Donald F / Schatz, David G

European journal of immunology

2019 Volume 50, Issue 3, Page(s) 380–395

Abstract: Secondary diversification of the Ig repertoire occurs through somatic hypermutation (SHM), gene conversion (GCV), and class switch recombination (CSR)-three processes that are initiated by activation-induced cytidine deaminase (AID). AID targets Ig genes ...

Abstract	Secondary diversification of the Ig repertoire occurs through somatic hypermutation (SHM), gene conversion (GCV), and class switch recombination (CSR)-three processes that are initiated by activation-induced cytidine deaminase (AID). AID targets Ig genes at orders of magnitude higher than the rest of the genome, but the basis for this specificity is poorly understood. We have previously demonstrated that enhancers and enhancer-like sequences from Ig genes are capable of stimulating SHM of neighboring genes in a capacity distinct from their roles in increasing transcription. Here, we use an in vitro proteomics approach to identify E-box, MEF2, Ets, and Ikaros transcription factor family members as potential binders of these enhancers. ChIP assays in the hypermutating Ramos B cell line confirmed that many of these factors bound the endogenous Igλ enhancer and/or the IgH intronic enhancer (Eμ) in vivo. Further investigation using SHM reporter assays identified binding sites for E2A and MEF2B in Eμ and demonstrated an association between loss of factor binding and decreases in the SHM stimulating activity of Eμ mutants. Our results provide novel insights into trans-acting factors that dictate SHM targeting and link their activity to specific DNA binding sites within Ig enhancers.
MeSH term(s)	Animals ; Chickens ; Genes, Immunoglobulin ; Humans ; Somatic Hypermutation, Immunoglobulin/physiology ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	Transcription Factors
Language	English
Publishing date	2019-12-19
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.201948357
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Zs.A 489: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Dickkopf-2 regulates the stem cell marker LGR5 in colorectal cancer via HNF4α1.

Shin, Jae Hun / Jeong, Jaekwang / Choi, Jungmin / Lim, Jaechul / Dinesh, Ravi K / Braverman, Jonathan / Hong, Jun Young / Maher, Stephen E / Amezcua Vesely, Maria C / Kim, WonJu / Koo, Ja-Hyun / Tang, Wenwen / Wu, Dianqing / Blackburn, Holly N / Xicola, Rosa M / Llor, Xavier / Yilmaz, Omer / Choi, Je-Min / Bothwell, Alfred L M

iScience

2021 Volume 24, Issue 5, Page(s) 102411

Abstract: Enhanced stemness in colorectal cancer has been reported and it contributes to aggressive progression, but the underlying mechanisms remain unclear. Here we report a Wnt ligand, Dickkopf-2 (DKK2) is essential for developing colorectal cancer stemness. ... ...

Abstract	Enhanced stemness in colorectal cancer has been reported and it contributes to aggressive progression, but the underlying mechanisms remain unclear. Here we report a Wnt ligand, Dickkopf-2 (DKK2) is essential for developing colorectal cancer stemness. Genetic depletion of
Language	English
Publishing date	2021-04-15
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2021.102411
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Article ; Online: Disease-associated CTNNBL1 mutation impairs somatic hypermutation by decreasing nuclear AID.

The Journal of clinical investigation

2020 Volume 130, Issue 8, Page(s) 4411–4422

Abstract: Patients with common variable immunodeficiency associated with autoimmune cytopenia (CVID+AIC) generate few isotype-switched B cells with severely decreased frequencies of somatic hypermutations (SHMs), but their underlying molecular defects remain ... ...

Abstract	Patients with common variable immunodeficiency associated with autoimmune cytopenia (CVID+AIC) generate few isotype-switched B cells with severely decreased frequencies of somatic hypermutations (SHMs), but their underlying molecular defects remain poorly characterized. We identified a CVID+AIC patient who displays a rare homozygous missense M466V mutation in β-catenin-like protein 1 (CTNNBL1). Because CTNNBL1 binds activation-induced cytidine deaminase (AID) that catalyzes SHM, we tested AID interactions with the CTNNBL1 M466V variant. We found that the M466V mutation interfered with the association of CTNNBL1 with AID, resulting in decreased AID in the nuclei of patient EBV-transformed B cell lines and of CTNNBL1 466V/V Ramos B cells engineered to express only CTNNBL1 M466V using CRISPR/Cas9 technology. As a consequence, the scarce IgG+ memory B cells from the CTNNBL1 466V/V patient showed a low SHM frequency that averaged 6.7 mutations compared with about 18 mutations per clone in healthy-donor counterparts. In addition, CTNNBL1 466V/V Ramos B cells displayed a decreased incidence of SHM that was reduced by half compared with parental WT Ramos B cells, demonstrating that the CTNNBL1 M466V mutation is responsible for defective SHM induction. We conclude that CTNNBL1 plays an important role in regulating AID-dependent antibody diversification in humans.
MeSH term(s)	Amino Acid Substitution ; Apoptosis Regulatory Proteins/genetics ; Apoptosis Regulatory Proteins/immunology ; B-Lymphocytes/immunology ; B-Lymphocytes/pathology ; Cell Line ; Child, Preschool ; Common Variable Immunodeficiency/genetics ; Common Variable Immunodeficiency/immunology ; Common Variable Immunodeficiency/pathology ; Cytidine Deaminase/genetics ; Cytidine Deaminase/immunology ; Female ; Homozygote ; Humans ; Immunologic Memory/genetics ; Mutation, Missense ; Nuclear Proteins/genetics ; Nuclear Proteins/immunology ; Somatic Hypermutation, Immunoglobulin
Chemical Substances	Apoptosis Regulatory Proteins ; CTNNBL1 protein, human ; Nuclear Proteins ; AICDA (activation-induced cytidine deaminase) (EC 3.5.4.-) ; Cytidine Deaminase (EC 3.5.4.5)
Language	English
Publishing date	2020-06-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI131297
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Article ; Online: CD8+ Tregs in lupus, autoimmunity, and beyond.

Dinesh, Ravi K / Skaggs, Brian J / La Cava, Antonio / Hahn, Bevra H / Singh, Ram Pyare

Autoimmunity reviews

2010 Volume 9, Issue 8, Page(s) 560–568

Abstract: While CD4(+)CD25(high) regulatory T cells (Tregs) have garnered much attention for their role in the maintenance of immune homeostasis, recent findings have shown that subsets of CD8(+) T cells (CD8(+) Tregs) display immunoregulatory functions as well. ... ...

Abstract	While CD4(+)CD25(high) regulatory T cells (Tregs) have garnered much attention for their role in the maintenance of immune homeostasis, recent findings have shown that subsets of CD8(+) T cells (CD8(+) Tregs) display immunoregulatory functions as well. Both CD4(+) Tregs and CD8(+) Tregs appear impaired in number and/or function in several autoimmune diseases and in experimental animal models of autoimmunity, suggesting the possibility of immunotherapeutic targeting of these cells for improved management of autoimmune conditions. Our group has developed a strategy to induce CD8(+) Tregs in autoimmune mice through the use of a tolerogenic self-peptide, and new information has been gained on the phenotype, function and role of induced CD8(+) Tregs in autoimmunity. Here we present an overview of the role and mechanisms of action of CD8(+) Tregs in autoimmunity, with a special focus on lupus. We also discuss the potential role of CD8(+) Tregs in other diseases, including chronic infection and cancer.
MeSH term(s)	Animals ; Autoimmunity/immunology ; CD8-Positive T-Lymphocytes/immunology ; Humans ; Lupus Erythematosus, Systemic/immunology ; Mice ; T-Lymphocyte Subsets/immunology ; T-Lymphocytes, Regulatory/immunology
Language	English
Publishing date	2010-04-10
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2144145-5
ISSN	1873-0183 ; 1568-9972
ISSN (online)	1873-0183
ISSN	1568-9972
DOI	10.1016/j.autrev.2010.03.006
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