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UNG shapes the specificity of AID-induced somatic hypermutation

ABSTRACT: This SuperSeries is composed of the following subset Series: GSE39108: UNG shapes the specifity of AID-induced somatic hypermutation in non B cells GSE39114: UNG shapes the specifity of AID-induced somatic hypermutation in B cells Refer to individual Series

ORGANISM(S): Mus musculus

SUBMITTER: Pablo Perez-Duran

PROVIDER: E-GEOD-39115 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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UNG shapes the specificity of AID-induced somatic hypermutation.

Pérez-Durán Pablo P Belver Laura L de Yébenes Virginia G VG Delgado Pilar P Pisano David G DG Ramiro Almudena R AR

The Journal of experimental medicine 20120604 7

Secondary diversification of antibodies through somatic hypermutation (SHM) and class switch recombination (CSR) is a critical component of the immune response. Activation-induced deaminase (AID) initiates both processes by deaminating cytosine residues in immunoglobulin genes. The resulting U:G mismatch can be processed by alternative pathways to give rise to a mutation (SHM) or a DNA double-strand break (CSR). Central to this processing is the activity of uracil-N-glycosylase (UNG), an enzyme ...[more]

PMID: 22665573

Similar Datasets

UNG shapes the specifity of AID-induced somatic hypermutation in non B cells

Project description:Secondary diversification of antibodies through somatic hypermutation (SHM) and class switch recombination (CSR) is a critical component of the immune response. Activation-induced deaminase (AID) initiates both processes by deaminating cytosine residues in immunoglobulin genes. The resulting U:G mismatch can be processed by alternative pathways to give rise to a mutation (SHM) or a DNA double-strand break (CSR). Central to this processing is the activity of uracil-N-glycosylase (UNG), an enzyme normally involved in error-free base excision repair. We used next generation sequencing to analyze the contribution of UNG to the resolution of AID-induced lesions. Loss- and gain-of-function experiments showed that UNG activity can promote both error-prone and high fidelity repair of U:G lesions. Unexpectedly, the balance between these alternative outcomes was influenced by the sequence context of the deaminated cytosine, with individual hotspots exhibiting higher susceptibility to UNG-triggered error-free or error-prone resolution. These results reveal UNG as a new molecular layer that shapes the specificity of AID-induced mutations and may provide new insights into the role of AID in cancer development. Next Generation Sequencing analysis of mutations introduced by AID in non B cells. NIH-3T3 cells were co-transduced with mOrangeSTOP and AID-ERM-bM-^@M-^Sexpressing vectors, together with Ugi (UNG inhibitor), UNG, or empty vector as control (n=3). Transduced cells were cultured in the presence of OHT during 11 d. AID-E58Q-ER vector (catalytically inactive form of AID) was used as a negative control in combination with the previously described constructions (n=3).

2012-07-04 | E-GEOD-39108 | biostudies-arrayexpress

UNG shapes the specifity of AID-induced somatic hypermutation in B cells

Project description:Secondary diversification of antibodies through somatic hypermutation (SHM) and class switch recombination (CSR) is a critical component of the immune response. Activation-induced deaminase (AID) initiates both processes by deaminating cytosine residues in immunoglobulin genes. The resulting U:G mismatch can be processed by alternative pathways to give rise to a mutation (SHM) or a DNA double-strand break (CSR). Central to this processing is the activity of uracil-N-glycosylase (UNG), an enzyme normally involved in error-free base excision repair. We used next generation sequencing to analyze the contribution of UNG to the resolution of AID-induced lesions. Loss- and gain-of-function experiments showed that UNG activity can promote both error-prone and high fidelity repair of U:G lesions. Unexpectedly, the balance between these alternative outcomes was influenced by the sequence context of the deaminated cytosine, with individual hotspots exhibiting higher susceptibility to UNG-triggered error-free or error-prone resolution. These results reveal UNG as a new molecular layer that shapes the specificity of AID-induced mutations and may provide new insights into the role of AID in cancer development. Next Generation Sequencing analysis of mutations introduced by AID in activated B lymphocytes from WT and UNG-/- mice (n=4). Activated B cells from AID-/- mice (n=2) were used as negative controls.

2012-07-04 | E-GEOD-39114 | biostudies-arrayexpress

Project description:UNG shapes the specificity of AID-induced somatic hypermutation

| PRJNA170045 | ENA

UNG shapes the specifity of AID-induced somatic hypermutation in non B cells

2012-07-05 | GSE39108 | GEO

UNG shapes the specifity of AID-induced somatic hypermutation in B cells

2012-07-05 | GSE39114 | GEO

Mus musculus

Project description:UNG shapes the specifity of AID-induced somatic hypermutation in B cells

| PRJNA170049 | ENA

Mus musculus

Project description:UNG shapes the specifity of AID-induced somatic hypermutation in non B cells

| PRJNA170048 | ENA

Genome-wide expression analysis in normal and immortalised and transformed human cell lines

Project description:Analysis of expression changes in the fetal human lung fibroblast cell line MRC5 over time (two time points: 50 and 100 population doublings) during immortalisation with the catalytic component of telomerase (hTERT) and in vitro transformation with SV40 Large T antigen and oncogenic H-RAS

2013-11-11 | E-MTAB-2003 | biostudies-arrayexpress

Gene expression analysis of B cell lymphomas from representative IÂµHABcl6, IÂµHABcl6 Ung-/- Msh2-/-, and IÂµHABcl6 Msh2-/- mouse models.

Project description:Somatic hypermutation (SHM) and class switch recombination (CSR) of immunoglobulin (Ig) genes are genomic modification events that occur in germinal center (GC) B cells and are initiated through deamination of cytidine to uracil by activation induced cytidine deaminase (AID). Resulting uracil-guanine (U-G) mismatches are subsequently processed by low-fidelity base-excision (BER) and mismatch repair (MMR) pathways to yield mutations and DNA strand lesions. Although off-target AID activity also contributes to oncogenic point mutations and chromosome translocations associated with B cell lymphomas, the role of downstream AID-associated DNA repair pathways in the pathogenesis of these lymphomas is unknown. Here, we show that simultaneous BER and MMR deficiency causes genomic instability and a shorter latency to the development of a BCL6-driven GC B cell lymphoma. In contrast, loss of BER alone is highly protective against B cell transformation while loss of MMR fosters the development of a variety of malignancies. These findings lend insight into a complex interplay between AID-associated BER and MMR pathways that produces a net protective effect against GC B cell lymphomagenesis. Representative B cell lymphomas from 3 IÂµHABcl6, 6 IÂµHABcl6 Ung-/- Msh2-/-, and 5 IÂµHABcl6 Msh2-/- mice were analyzed in this study. Total RNA was extracted from frozen tumor cells and processed according to Illumina standard protocols.

2015-12-08 | E-GEOD-48304 | biostudies-arrayexpress

Genome-wide DNA methylation analysis of promoters in normal and immortalised and transformed human cell lines

Project description:Analysis of DNA methylation changes at promoters in the fetal human lung fibroblast cell line MRC5 over time (two time points: 50 and 100 population doublings) during immortalisation with the catalytic component of telomerase (hTERT) and in vitro transformation with SV40 Large T antigen and oncogenic H-RAS

2013-11-11 | E-MTAB-2005 | biostudies-arrayexpress

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