In eukaryotes, the MRN/X (Mre11, Rad50 and Nbs1/Xrs2) complex initiates the end resection in cooperation with CtIP/Sae2. End resection of DSBs proceeds in two steps, an initial resection followed by a more extensive one. Rad51 filaments on ssDNA invade homologous DNA duplexes, generating D-loops and subsequently forming double Holliday junctions. The ssDNA becomes coated with RPA molecules, which are then replaced by Rad51. In this study, we investigated the hypothesis that WRN-1 mediates end resection of DSBs and as a result extends the length of ssDNA available for binding RPA.ĭouble-strand DNA breaks are resected at their 5′-ends to produce 3′-ended ssDNA, as a preparatory step for DSB repair via homologous recombination (HR). However, the mechanism by which it promotes the formation of RPA foci in response to DSBs is not clear. We previously proposed that in response to stalled replication forks, WRN-1 activates the ATR homolog by increasing the stability of RPA on single strand DNA (ssDNA). The WRN-1 helicase mediates checkpoint activation in response to stalled replication forks and DSBs, by promoting the accumulation of replication protein A (RPA) and activating ATM and ATR homologs downstream of RPA. In the model organism Caenorhabditis elegans, WRN-1 contains the helicase domain but not the exonuclease domain. In mammals, WRN is also required to activate cell cycle checkpoints in response to stalled DNA replication forks and interstrand DNA crosslinks. In addition, it promotes the expression of microRNA miR-124, so affecting the expression of many genes targeted by that microRNA. In mammals, WRN participates in double-strand DNA break (DSB) repair, base excision repair, replication fork recovery, and telomere maintenance. The protein responsible for the syndrome is Werner syndrome protein (WRN) which has two enzymatic activities: DNA helicase and exonuclease. The rare genetic disease, Werner syndrome, is associated with premature aging and an increased incidence of cancer, as well as genomic instability at the cellular level.
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