The nature of mutations induced by replication–transcription collisions

• Published in: Nature (London) Vol. 535; no. 7610; pp. 178 - 181
• Main Authors: Sankar, T. Sabari, Wastuwidyaningtyas, Brigitta D., Dong, Yuexin, Lewis, Sarah A., Wang, Jue D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.07.2016; Nature Publishing Group
• Subjects: 38/22; 38/23; 38/70; 38/77; 45/29; 45/90; 631/208/325/2482; 631/208/737/211; 631/337/151; 631/337/572/2102; Adenosine - genetics; Adenosine - metabolism; Bacillus subtilis - genetics; Cell division; Deamination; Deoxyribonucleic acid; DNA; DNA Mutational Analysis; DNA Replication - genetics; Gene expression; Gene mutations; Genetic disorders; Genetic transcription; Genomes; Humanities and Social Sciences; Hypoxanthine - metabolism; INDEL Mutation - genetics; letter; Models, Genetic; multidisciplinary; Mutagenesis; Mutagenesis - genetics; Mutation; Mutation - genetics; Mutation Rate; Observations; Promoter Regions, Genetic - genetics; Repetitive Sequences, Nucleic Acid - genetics; RNA polymerase; Science; Sequence Deletion - genetics; Sigma Factor - metabolism; Templates, Genetic; Transcription, Genetic - genetics
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature18316

When transcription and replication machineries collide on DNA, they can cause mutations to occur in the area near the collision; these mutations are now shown to include two types—duplications/deletions within the transcription unit and base substitutions in the cis -regulatory element of gene expression. When replication and transcription tangle When the transcription and replication machineries collide on DNA, mutations can occur in the area near the collision. Jue Wang and colleagues show that these mutations are of two types: duplications/deletions within the transcription unit and promoter-localized base substitutions. This second type of mutation primarily reflects a previously unknown vulnerability of the conserved −7 A nucleotide of the thyP3 promoter, which is solvent-exposed in the transcription initiation complex and may therefore be subject to spontaneous deamination. Deamination converts A to hypoxanthine, which pairs with C, to introduce a T to C substitution at this position. The DNA replication and transcription machineries share a common DNA template and thus can collide with each other co-directionally or head-on 1 , 2 . Replication–transcription collisions can cause replication fork arrest, premature transcription termination, DNA breaks, and recombination intermediates threatening genome integrity 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 . Collisions may also trigger mutations, which are major contributors to genetic disease and evolution 5 , 7 , 11 . However, the nature and mechanisms of collision-induced mutagenesis remain poorly understood. Here we reveal the genetic consequences of replication–transcription collisions in actively dividing bacteria to be two classes of mutations: duplications/deletions and base substitutions in promoters. Both signatures are highly deleterious but are distinct from the previously well-characterized base substitutions in the coding sequence. Duplications/deletions are probably caused by replication stalling events that are triggered by collisions; their distribution patterns are consistent with where the fork first encounters a transcription complex upon entering a transcription unit. Promoter substitutions result mostly from head-on collisions and frequently occur at a nucleotide that is conserved in promoters recognized by the major σ factor in bacteria. This substitution is generated via adenine deamination on the template strand in the promoter open complex, as a consequence of head-on replication perturbing transcription initiation. We conclude that replication–transcription collisions induce distinct mutation signatures by antagonizing replication and transcription, not only in coding sequences but also in gene regulatory elements.