Host: The Japan Radiation Research Society, Chairman of the 52nd Annual Meeting, Toshiteru Okubo (Radiation Effects Research Foundation)
Werner syndrome is an autosomal recessive disorder associated with premature aging and cancer predisposition caused by mutation of WRN gene. WRN is a member of the RecQ DNA helicase family with functions in maintaining genome stability. Werner syndrome cells show the sensitivities to several DNA damage, suggesting that WRN mights works in DNA damage response. Here, we investigated the role of WRN in several kinds of DNA damage responses using Werner syndrome cells and NBS and AT cells. We also examined the role of DSB repair and TLS DNA synthesis.
WRN rapidly formed discrete nuclear foci dependently on NBS1 following DNA damage. NBS1 physically interacted with WRN through its FHA domain and important for the phosphorylation of WRN. WRN formed DNA damage-dependent foci during S phase, but not in G1 phase. However, Werner cells showed the homologous recombination activity at normal level, although HR repair functions preferentially during S phase. WRN also interact with PCNA without DNA damage, but the generation of DNA damage let WRN dissociate from PCNA and caused the ubiquitination of PCNA, which is essential to tlanslesion DNA synthesis. WS cells showed constitutive ubiquitination of PCNA and interaction between PCNA and Rad18 E3 ligase without DNA damage. Taken together, WRN might mediate the interaction of PCNA with Rad18 and the subsequent ubiquitination of PCNA, and could be involved in the regulation of TLS to prevent mutation.
