Periodic Reporting for period 1 - RAGES (Molecular determination of Rif1-Associated Genomic Elements and their function in regulating genome activity and integrity)
Période du rapport: 2016-03-31 au 2018-03-30
Understanding the molecular function of the RIF1 protein is paramount, as mis-regulation of DSB repair at the level of Rif1/53BP1-deficiency manifests in primary immunodeficiency in mammals. Conversely, an inability to counteract Rif1/53BP1- dependent activities during DNA repair is associated with genomic instability that drives carcinogenesis. Interestingly, evidence suggests that Rif1 may also mediate gene-repression, raising the possibility that common Rif1-dependent mechanisms may regulate gene transcription and DNA repair.
In examining: (1) the chromosomal contexts in which Rif1 operates; (2) the factors with which Rif1 cooperates; and (3) the phenotypic consequences of Rif1 loss; this proposal set out to test the overarching hypothesis that a common activity exerted by the Rif1 protein in chromatin plays a vital role in regulating both gene silencing and DNA repair activities. Thus successful completion of this project aims to discover vital, yet hitherto undefined mechanism that may link genome activity and stability.
In parallel, collaborative published work performed as part of the RAGES MSCIF action contributed to a better understanding of cell-cycle control by the Rif1-interacting protein 53BP1, its upstream regulator during DNA repair, via its function as a p53-regulatory protein (doi: 10.1016/j.molcel.2016.08.002.).