The connection between transcription and genomic instability

Abstract

Transcription is a central aspect of DNA metabolism that takes place on the same substrate as replication, repair and recombination. Not surprisingly, therefore, there is a physical and functional connection between these processes. In recent years, transcription has proven to be a relevant player in the maintenance of genome integrity and in the induction of genetic instability and diversity. The aim of this review is to provide an integrative view on how transcription can control different aspects of genomic integrity, by exploring different mechanisms that might be responsible for transcription-associated mutation (TAM) and transcription-associated recombination (TAR).

Fig. 1. Possible transcription-associated recombination mechanisms. (A) The replication fork could be stalled by an elongating or blocked RNAPII advancing in the opposite direction (left) or advancing in the same direction but blocked as a consequence of putative DNA–RNA hybrids (R loop) formed by the nascent RNA coming out from the RNAPII ahead (right). (B) The stalled replication fork can lead to recombinogenic 3′-ended ssDNA by fork reversal, leading to a HJ, or by a nick in the template DNA (left). The R loop can lead to recombinogenic ends by damage to the ssDNA template and posterior replication (right). The ssDNA region would be a consequence of the unfinished replication of the lagging strand. (C) Recombination could occur by strand invasion followed by replication, if only one 3′-ssDNA end is involved, or by a DSB repair mechanism, which can potentially be error prone. The latter could also explain some cases of transcription-associated mutation. A yellow box indicates the recombinogenic 3′-ssDNA ends. In (A) and (B), newly synthesized strands are shown in blue. In (C), different molecules are shown in red and blue to better visualize the recombinant products, irrespective of the newly synthesized strand.