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Evaluation of potential role of R-loop and G-quadruplex DNA in the fragility of c-MYC during chromosomal translocation associated with Burkitt's lymphoma

Kumari, N and Das, K and Sharma, S and Dahal, S and Desai, SS and Roy, U and Sharma, A and Manjunath, M and Gopalakrishnan, V and Retheesh, ST and Javadekar, SM and Choudhary, B and Raghavan, SC (2023) Evaluation of potential role of R-loop and G-quadruplex DNA in the fragility of c-MYC during chromosomal translocation associated with Burkitt's lymphoma. In: Journal of Biological Chemistry, 299 (12).

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Official URL: https://doi.org/10.1016/j.jbc.2023.105431


t(8;14) translocation is the hallmark of Burkitt's lymphoma and results in c-MYC deregulation. During the translocation, c-MYC gene on chromosome 8 gets juxtaposed to the Ig switch regions on chromosome 14. Although the promoter of c-MYC has been investigated for its mechanism of fragility, little is known about other c-MYC breakpoint regions. We have analyzed the translocation break points at the exon 1/intron 1 of c-MYC locus from patients with Burkitt's lymphoma. Results showed that the breakpoint region, when present on a plasmid, could fold into an R-loop confirmation in a transcription-dependent manner. Sodium bisulfite modification assay revealed significant single-strandedness on chromosomal DNA of Burkitt's lymphoma cell line, Raji, and normal lymphocytes, revealing distinct R-loops covering up to 100 bp region. Besides, ChIP-DRIP analysis reveals that the R-loop antibody can bind to the breakpoint region. Further, we show the formation of stable parallel intramolecular G-quadruplex on non-template strand of the genome. Finally, incubation of purified AID in vitro or overexpression of AID within the cells led to enhanced mutation frequency at the c-MYC breakpoint region. Interestingly, anti-γH2AX can bind to DSBs generated at the c-MYC breakpoint region within the cells. The formation of R-loop and G-quadruplex was found to be mutually exclusive. Therefore, our results suggest that AID can bind to the single-stranded region of the R-loop and G4 DNA, leading to the deamination of cytosines to uracil and induction of DNA breaks in one of the DNA strands, leading to double-strand break, which could culminate in t(8;14) chromosomal translocation. © 2023 The Authors

Item Type: Journal Article
Publication: Journal of Biological Chemistry
Publisher: American Society for Biochemistry and Molecular Biology Inc.
Additional Information: The copyright for this article belongs to Author
Keywords: Amines; Cell culture; Oncology; Transcription, AID; Chromosomal aberration; Cytidine deaminase; DNA double strand breaks; G-quartet; Genomic instability; R-loop; RNA-DNA hybrids; RNase H; T(8;14) translocation, DNA, activation induced cytidine deaminase; bisulfite; guanine quadruplex; histone H2AX; single stranded DNA, animal cell; Article; Burkitt lymphoma; chromatin immunoprecipitation; chromosome rearrangement; chromosome translocation; controlled study; DNA RNA hybridization; double stranded DNA break; embryo; gene mutation; genetic association; genome; human; human cell; in vitro study; infant; lymphocyte; mouse; mutation rate; nonhuman; oncogene c myc; pathogenesis; protein expression; R loop; Raji cell line
Department/Centre: Division of Biological Sciences > Biochemistry
Date Deposited: 29 Feb 2024 05:54
Last Modified: 29 Feb 2024 05:54
URI: https://eprints.iisc.ac.in/id/eprint/83726

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