The role of chromatin modifications in genomic stability and immune diversity

Abstract

Chromatin architecture is constantly remodelled, to overcome DNA damage, induce immune diversification and ensure gene transcription and replication. If genome remodelling is not accurately regulated, cells can face detrimental consequences, such as apoptosis and transformation, with potential tumorigenesis and premature aging. Global understanding of how chromatin remodelling is regulated and modulated is an ongoing key challenge for the development of potential therapies for all pathological conditions generated by genome instability. AID/APOBECs are powerful DNA mutators, whose activity is fundamental for the establishment of adequate innate and adaptive immune defences. The mechanisms regulating their upstream activity remain elusive. Here, a link between H3K7me2 histone modification and AID activity in B cells has been identified. Downstream of DNA mutators, helicases are ubiquitously involved in the unwinding of DNA double strands, allowing the consequent targeting of other DNA modifying proteins. Their role is therefore pivotal in genome replication, repair and recombination, and understanding their activity is a major goal. Here, a fluorescence based toolkit have been elaborated to visualise and quantify helicases activity on DNA substrates. Among all DNA damages, double strand breaks are particularly dangerous as they can lead to loss of genetic material. A complete elucidation of the different mechanisms of their repair is an ongoing challenge. Here, the putative helicase RuvBL2 was identified as a potential contributor of the homology-directed repair pathway. All these findings provide new important details for the elucidation of the role of DNA metabolizing enzymes and remodellers in the maintenance of genome stability with potential applications to immune diversity.