The RNA tether model for human chromosomal translocation fragile zones

Di Liu; Chih-Lin Hsieh; Michael R Lieber

doi:10.1016/j.tibs.2024.02.003

The RNA tether model for human chromosomal translocation fragile zones

Trends Biochem Sci. 2024 May;49(5):391-400. doi: 10.1016/j.tibs.2024.02.003. Epub 2024 Mar 14.

Authors

Di Liu¹, Chih-Lin Hsieh², Michael R Lieber³

Affiliations

¹ Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, and Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi 710061, China.
² USC Norris Comprehensive Cancer Center, Department of Urology, University of Southern California, Los Angeles, CA 90089-9176, USA.
³ USC Norris Comprehensive Cancer Center, Departments of Pathology and Laboratory Medicine, of Molecular Microbiology and Immunology, of Biochemistry and Molecular Medicine, and in the Section of Molecular and Computational Biology, University of Southern California, Los Angeles, CA 90089-9176, USA. Electronic address: lieber@usc.edu.

PMID: 38490833
PMCID: PMC11069435 (available on 2025-05-01)
DOI: 10.1016/j.tibs.2024.02.003

Abstract

One of the two chromosomal breakage events in recurring translocations in B cell neoplasms is often due to the recombination-activating gene complex (RAG complex) releasing DNA ends before end joining. The other break occurs in a fragile zone of 20-600 bp in a non-antigen receptor gene locus, with a more complex and intriguing set of mechanistic factors underlying such narrow fragile zones. These factors include activation-induced deaminase (AID), which acts only at regions of single-stranded DNA (ssDNA). Recent work leads to a model involving the tethering of AID to the nascent RNA as it emerges from the RNA polymerase. This mechanism may have relevance in class switch recombination (CSR) and somatic hypermutation (SHM), as well as broader relevance for other DNA enzymes.

Keywords: APOBEC; DNA methylation; activation-induced deaminase (AID); double-strand break (DSB); nascent RNA; non-homologous end joining (NHEJ).

Publication types

Review
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Chromosome Fragile Sites
Cytidine Deaminase / genetics
Cytidine Deaminase / metabolism
Humans
RNA* / genetics
RNA* / metabolism
Translocation, Genetic*

Substances

RNA
Cytidine Deaminase
AICDA (activation-induced cytidine deaminase)

Abstract

Publication types

MeSH terms

Substances

Grants and funding