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Mutations at Exon 4 Associated with T Cell Acute Lymphoblastic Leukemia Are Facilitated by AID and Formation of Non-B DNA Conformations. | LitMetric

AI Article Synopsis

  • The deregulation of a specific transcription factor is key in the development of T cell acute lymphoblastic leukemia (T-ALL), mainly due to mutations in exon 4 that disrupt its DNA-binding ability.
  • The study highlights the role of Activation-induced cytidine deaminase (AID) in mutagenesis, showing that AID is present in T-ALL cells and creates distinct mutation patterns by binding to fragile regions in the DNA.
  • AID's binding leads to the formation of complex DNA structures that can cause errors during replication, ultimately resulting in harmful mutations that impair the transcription factor's function and contribute to the onset of T-ALL.

Article Abstract

One of the primary reasons behind the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL) is the deregulation of the transcription factor . The exon 4 of harbors several driver mutations, which abolishes its DNA-binding ability. The high frequency of C > T or G > A conversion in close vicinity of AID (Activation-induced cytidine deaminase)-hotspot motifs in the deregulated gene prompted us to investigate the role of AID in mutagenesis. Our results reveal that AID is expressed in T-ALL patient-derived cells, binds to fragile region (FR) in exon 4 of T cells in vivo, and generates a signature mutation pattern in this region. The mutation frequency in could be modulated upon overexpression of the AID gene in the knockout background, further suggesting the involvement of AID in mutagenesis. Importantly, various lines of experimentation reveal that could fold into parallel G-quadruplex, triplex, and hairpin structures, which could act as a replication/transcription block, causing mutagenesis. Thus, our results suggest that AID binds to exon 4 due to non-B DNA formation, causing U:G mismatches or replication blocks, which, when repaired erroneously, generates deleterious mutations, resulting in loss of functionality of , and thus becomes the cause of T-ALL.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11583620PMC
http://dx.doi.org/10.1080/10985549.2024.2419661DOI Listing

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