Chromosomal breaks at the origin of small tandem DNA duplications. (17th November 2022)

• Record Type: Journal Article
• Authors: Schimmel, Joost; van Wezel, Marloes D.; van Schendel, Robin; Tijsterman, Marcel
• Is Part Of: BioEssays. Volume 45:Number 1(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-11-17
• Subjects: clustered single‐strand breaks -- DNA polymerases -- double‐strand breaks -- FLT3‐ITD -- non‐homologous end‐joining -- small tandem duplications; Molecular biology -- Periodicals; Cytology -- Periodicals; Developmental biology -- Periodicals; 572.8
• DOI: 10.1002/bies.202200168
• Languages: English
• ISSNs: 0265-9247

Abstract

Abstract: Small tandem DNA duplications in the range of 15 to 300 base‐pairs play an important role in the aetiology of human disease and contribute to genome diversity. Here, we discuss different proposed mechanisms for their occurrence and argue that this type of structural variation mainly results from mutagenic repair of chromosomal breaks. This hypothesis is supported by both bioinformatical analysis of insertions occurring in the genome of different species and disease alleles, as well as by CRISPR/Cas9‐based experimental data from different model systems. Recent work points to fill‐in synthesis at double‐stranded DNA breaks with complementary sequences, regulated by end‐joining mechanisms, to account for small tandem duplications. We will review the prevalence of small tandem duplications in the population, and we will speculate on the potential sources of DNA damage that could give rise to this mutational signature. With the development of novel algorithms to analyse sequencing data, small tandem duplications are now more frequently detected in the human genome and identified as oncogenic gain‐of‐function mutations. Understanding their origin could lead to optimized treatment regimens to prevent therapy‐induced activation of oncogenes and might expose novel vulnerabilities in cancer. Abstract : Small tandem DNA duplications form a specific mutational signature frequently found in human disease alleles and cancer genes. Here we hypothesize that these duplications mainly arise at chromosomal DNA breaks that result from two closely located single‐stranded nicks, through error‐prone repair by the non‐homologous end‐joining pathway.