The cell response to replicationdefects affects alternative splicing programs and cell morphology

Cells established from a patient with hypomorphic mutations of DNA ligase I gene show a delay in the maturation of replicative intermediates resulting in the accumulation of single and double-stranded breaks. In these cells the ataxia telangiectasia mutated protein kinase (ATM) and its downstream kinase Chk2 are constitutively phosphorylated at a basal level (1). Using DNA ligase I-defective 46BR.1G1 cells as system model to study the cell response to replication-mediated DNA damage, we have recently demonstrated that the damage elicited by DNA ligase I deficiency causes a change in the phosphorylation pattern of the alternative splicing factor SRSF1 (SF2/ASF). As a consequence, SRSF1 target transcripts, such as the tumorigenic Recepteur d'Origine Nantais (RON) and Caspase 9, undergo a change in their alternative splicing program allowing the survival of damaged cells (2). The basal level of ATM activation is also required to promote a change of cell morphology unveiling a link between replication defects and the structural organization of the cell. 1. Soza S., Leva V. et al. Mol Cell Biol (2009) 29:2032-41 2. Leva V., Giuliano S. et al Nucleic Acids Res (2012) 40:1106-17