Nonimmunoglobulin target loci of activation-induced cytidine deaminase (AID) share unique features with immunoglobulin genes

Kato, Lucia; Begum, Noorzahan; Burroughs, A. Maxwell; Doi, Tomomitsu; Kawai, Jun; Daub, Carsten O.; Kawaguchi, Takahisa; Matsuda, Fumihiko; Hayashizaki, Yoshihide; Honjo, Tasuku

doi:10.1073/pnas.1120791109

Cited by 67 publications

(76 citation statements)

References 61 publications

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“…In CSR, FACT contributes to the DNA break by promoting the trimethylation of H3K4 (16). Regarding SHM, we reported that H3K4me3 is enriched in SHM target regions (5). However, as H3K4me3 is a common modification on active chromatin, the targeting mechanism for CSR and SHM cannot be fully explained by the level of H3K4me3.…”

Section: Discussionmentioning

confidence: 69%

“…Therefore, we proposed that the H3K4me3 chromatin modification is a marker for CSR. We later showed that H3K4me3 also accumulates at SHM-targeted genomic regions, indicating that this histone modification is important for the induction of both CSR and SHM (5).…”

Section: Aid | Ssrp1mentioning

confidence: 83%

“…In BL2 cells, the non-Ig genes metastasis associated lung adenocarcinoma transcript 1 (Malat1) and small nucleolar RNA host gene 3 (Snhg3) are mutated at a similar level as the V(D)J region by the JP8Bdel-ER AID transgene (5). To evaluate the quantitative correlation between chromatin marking by FACT and H3.3 enrichment and SHM, we examined the FACT and H3.3 occupancies in these non-Ig SHM target regions.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, we speculate that the more frequently DNA is unwound from the nucleosome, the higher the chance of the DNA being hypermutated. We previously reported that H3K4me3 serves as a marker for SHM and CSR (5,16). In CSR, FACT contributes to the DNA break by promoting the trimethylation of H3K4 (16).…”

Section: Discussionmentioning

confidence: 99%

“…This highly specific SHM targeting can be partially explained by special DNA structures, such as the R-loop, G-quartet, and non-B structure, that can be produced during transcription at the target regions (1,3,4). In fact, mutation targets are flanked by non-B-prone DNA sequences, such as tandem repeats and inverted repeats (3,5). It has been proposed that non-B DNA structure can cause irreversible DNA cleavage by DNA Topoisomerase I, leading to generation of the DNA lesions responsible for class switch recombination (CSR) and SHM (3,6,7).…”

Section: Aid | Ssrp1mentioning

confidence: 99%

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Accumulation of the FACT complex, as well as histone H3.3, serves as a target marker for somatic hypermutation

Aida

Hamad

Stanlie

et al. 2013

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

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Somatic hypermutation (SHM) requires not only the expression of activation-induced cytidine deaminase, but also transcription in the target regions. However, how transcription guides activation-induced cytidine deaminase in targeting SHM to the Ig genes is not fully understood. Here, we found that the “facilitates chromatin transcription” (FACT) complex promotes SHM by RNAi screening of transcription elongation factors. Furthermore, FACT and histone H3.3, a hallmark of transcription-coupled histone turnover, are enriched at the V(D)J region, 5′ flanking sequence of the Sμ switch region and the light chain Jκ 5 segment region in the Ig loci. The regions with the most abundant deposition of FACT and H3.3 were also the most efficient targets of SHM. These results demonstrate the importance of histone-exchanging dynamics at the chromatin of SHM targets, especially in Ig genes.

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Section: Discussionmentioning

confidence: 69%

Section: Aid | Ssrp1mentioning

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Aid | Ssrp1mentioning

confidence: 99%

See 3 more Smart Citations

Accumulation of the FACT complex, as well as histone H3.3, serves as a target marker for somatic hypermutation

Aida

Hamad

Stanlie

et al. 2013

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

Self Cite

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Hit identification of novel small molecules interfering with MALAT1 triplex by a structure‐based virtual screening

Rocca

Polerà

Juli

et al. 2023

Archiv der Pharmazie

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Nowadays, RNA is an attractive target for the design of new small molecules with different pharmacological activities. Among several RNA molecules, long noncoding RNAs (lncRNAs) are extensively reported to be involved in cancer pathogenesis. In particular, the overexpression of lncRNA metastasisassociated lung adenocarcinoma transcript 1 (MALAT1) plays an important role in the development of multiple myeloma (MM). Starting from the crystallographic structure of the triple-helical stability element at the 3'-end of MALAT1, we performed a structure-based virtual screening of a large commercial database, previously filtered according to the drug-like properties.After a thermodynamic analysis, we selected five compounds for the in vitro assays. Compound M5, characterized by a diazaindene scaffold, emerged as the most promising molecule enabling the destabilization of the MALAT1 triplex structure and antiproliferative activity on in vitro models of MM. M5 is proposed as a lead compound to be further optimized for improving its affinity toward MALAT1.

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Molecular Subclusters of Follicular Lymphoma: A Report From the Uk's Haematological Malignancy Research Network

Crouch

Painter

Barrans

et al. 2021

Hematological Oncology

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= 43, 70, 124, by age respectively). All NHL sub-types were more common in males except for Mediastinal B-cell (PMBL) more common in females. For all NHLs combined, survival was not influenced by gender or age but differed by place of care. 2y OS of patients aged 15-24y treated at the 29 Consented Study hospitals was 86% and 74% at other, mostly smaller district hospitals, Hazard Ratio 1.75 (0.94, 3.26). Consented Study Cohort 392 patients were recruited , 15-19y (n = 111), 20-24y (n = 148), 25-29y (n = 133). 27 NHL sub-types were recorded. Presentation with advanced disease was common; of 104 DLBCLs, 15% had NCCI IPI score of 4-5 and 18% had ≥3 extranodal disease sites.Unexpected was frequent failure to respond to first-line therapy in DLBCL and PMBL. 8/81 (10%) DLBCLs with complete treatment records died with refractory disease and 9 (11%) required ≥2 lines to achieve remission. 4/60 (7%) PMBLs died with refractory disease and 19 (32%) remained PET positive after first-line chemotherapy, needing further chemotherapy or radiotherapy to achieve remission.There was variation between hospitals in treatment regimens used for individual diseases. The effect of treatment on survival being most marked for Burkitt's Lymphoma aged 15-24y. Of a total 32 cases, 23 were treated with (R)CODOX-M±IVAC, 7 died (OS 69%); 9 treated on the (R)FAB/LMB96 protocol, 1 died (OS 89%). This observation needs investigation in a randomised trial.Conclusions: NHL in teenage and young adult patients is challenging to manage. Advanced disease and resistance to first line treatment is common. Our findings support treatment of these cases guided by experienced cancer centres. The detailed information gained by this national collaboration provides the evidence base for future trials and treatment strategies.

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Nonimmunoglobulin target loci of activation-induced cytidine deaminase (AID) share unique features with immunoglobulin genes

Cited by 67 publications

References 61 publications

Accumulation of the FACT complex, as well as histone H3.3, serves as a target marker for somatic hypermutation

Accumulation of the FACT complex, as well as histone H3.3, serves as a target marker for somatic hypermutation

Hit identification of novel small molecules interfering with MALAT1 triplex by a structure‐based virtual screening

Molecular Subclusters of Follicular Lymphoma: A Report From the Uk's Haematological Malignancy Research Network

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