TET deficiency perturbs mature B cell homeostasis and promotes oncogenesis associated

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TET deficiency perturbs mature B cell homeostasis and promotes oncogenesis associated with accumulation of G-quadruplex and R-loop structures

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FROM: https://www.livescience.com/cancer-l...d-knots-in-dna Bizarre knotted DNA structures linked to cancer in mice By Nicoletta Lanese (2022-01-20) Missing enzymes may cause troublesome knots to appear in DNA. Oddly tangled and looped DNA structures could be linked to cancer, according to a new study in mice. DNA typically looks like a twisted ladder. But the loss of key enzymes in the body causes the genetic molecule to become tangled up in bizarre loops and knots, and at least in mice, these odd DNA structures may drive the development of cancer, The Scientist reported. Specifically, a family of enzymes known as ten-eleven translocation (TET) enzymes seems critical to preventing DNA from forming these troublesome knots, according to the study, published Dec. 22 in the journal Nature Immunology. TET enzymes jump-start a process that removes methyl groups — "chemical caps" consisting of three hydrogen atoms and one carbon atom — from the surface of DNA molecules. Methyl groups prevent specific genes within the DNA from being switched on, so by helping to remove these methyl groups, TET enzymes play key roles in regulating gene activity and development. However, studies suggest that when cells don't carry enough TET enzymes, this deficiency may contribute to the development of cancer. In white blood cells, in particular, research has revealed a strong correlation between a lack of TET enzymes and the onset of cancer, The Scientist reported... (SNIP)

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Original Paper:

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Quote:

FROM: https://www.nature.com/articles/s41590-021-01087-w.epdf TET deficiency perturbs mature B cell homeostasis and promotes oncogenesis associated with accumulation of G-quadruplex and R-loop structures Vipul Shukla Daniela Samaniego-Castruita Zhen Dong1, Edahí González-Avalos1, Qingqing Yan Kavitha Sarma and Anjana Rao (2021-12-20) Enzymes of the TET family are methylcytosine dioxygenases that undergo frequent mutational or functional inactivation in human cancers. Recurrent loss-of-function mutations in TET proteins are frequent in human diffuse large B cell lymphoma (DLBCL). Here, we investigate the role of TET proteins in B cell homeostasis and development of B cell lymphomas with features of DLBCL. We show that deletion of Tet2 and Tet3 genes in mature B cells in mice perturbs B cell homeostasis and results in spontaneous development of germinal center (GC)-derived B cell lymphomas with increased G-quadruplexes and R-loops. At a genome-wide level, G-quadruplexes and R-loops were associated with increased DNA double-strand breaks (DSBs) at immunoglobulin switch regions. Deletion of the DNA methyltransferase DNMT1 in TET-deficient B cells prevented expansion of GC B cells, diminished the accumulation of G-quadruplexes and R-loops and delayed B lymphoma development, consistent with the opposing functions of DNMT and TET enzymes in DNA methylation and demethylation. Clustered regularly interspaced short palindromic repeats (CRISPR)-mediated depletion of nucleases and helicases that regulate G-quadruplexes and R-loops decreased the viability of TET-deficient B cells. Our studies suggest a molecular mechanism by which TET loss of function might predispose to the development of B cell malignancies. The three mammalian TET enzymes (TET1, TET2 and TET3) are Fe(II)-, oxygen- and α-ketoglutarate-dependent dioxygenases that sequentially oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC)1–3. TET enzymes regulate enhancer activity and DNA methylation dynamics during development (including B cell development)4–8, cell differentiation and cell lineage specification (reviewed in refs. 9–12). TET2 gene mutations and/or decreased TET activity have been observed in many hematological malignancies and solid cancers, often through impaired regulation of metabolic enzymes that affect TET activity (reviewed in refs. 9,13–16). For instance, TET2 is recurrently mutated in ~10% of DLBCL17–19, a heterogeneous malignancy originating in mature B cells undergoing activation and differentiation in GCs. TET2 mutations represent an early driver event in DLBCL6; in mouse models, deletion of Tet2 in hematopoietic lineages disrupted GC B cell homeostasis and promoted development of more aggressive lymphomas when the transcription factor BCL6 was constitutively overexpressed6. 5hmC deposition has been observed at sites of DNA DSBs in HeLa cells20, and TET2 is associated with degradation of stalled replication forks in BRCA2-deficient mouse cells21, suggesting that TET proteins regulate genomic integrity. (SNIP)

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