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...vels peaking at S and G 2 and an increased sensitivity of cells from Bloom syndrome patient to DNA damage in S, but not G 1 phase, suggesting a pivotal role of BLM in response of replicational stress =-=(4, 13, 14, 17)-=-. Mechanisms activated during replication might actually repair the lesions that accumulate in G 1 in WRNdeficient cells. This could account for the relatively normal appearance of rapidly replicating...

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... ligand (31) and the importance of the ATR signaling pathway for their prevention. Upon stalled replication, ATR has been reported to phosphorylate and co-localize with the RecQ helicases WRN and BLM =-=(17,18,54)-=-, which both could unwind G-quadruplex structures (55,56). Moreover sister telomere losses, almost exclusively concerning the lagging strand telomeres, have been reported in cells lacking WRN helicase...

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... renaturation of complementary strands [37]. The endonuclease XPG is also reported to stimulate the annealing activity of the WRN helicase [99]. 5.5. Post-Translational Modification of Helicases. Catalytic activities of proteins can be modulated by posttranslational modifications, such as phosphorylation/dephosphorylation, acetylation, ubiquitination, and SUMOylation. For example, endogenous RECQ1 is phosphorylated upon treatment of cells with ionizing radiation (IR), Ultraviolet (UV), and hydroxyurea (HU) [100]; BLM is phosphorylated by ATM in response to IR [101, 102], ATR in response to HU [103], and several other kinases–CK1 [104], cdc2 [105], and MPS1 [106]. WRN is phosphorylated by ATM and ATR in response to replication fork arrest [107, 108]. BLM is a SUMO substrate and SUMO modification regulates BLM’s intranuclear localization [109]. WRN is acetylated by the acetyltransferase p300 [110]. HARP is phosphorylated by ATM, ATR, and DNA-PK in response to the DNA damage checkpoint [11, 81]. Indeed, the strand annealing activity of CSB is increased by dephosphorylation with phosphatase I and decreased by phosphorylation with CKII [58]. Thus, helicase function may in specific cases be r...

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... the chicken DT40 Bcell line display normal sensitivity to HU [29] whereas BS lymphoblastoid cells are resistant to HU-induced apoptosis [30], and BS GM08505 fibroblast cells are hypersensitive to HU =-=[31]-=-. In this paper, we used two different cellular models of BS to investigate the sensitivity of BLM-deficient cells to HU-induced replication stress. We show that BLM deficiency is not associated with ...

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...recombinational repair of double-strand breaks and elevated SCEs as seen in BS cells (36). In addition, BLM is phosphorylated by the ATR and ATM kinases, which are activated in response to DNA damage =-=(37,38)-=-. Interaction between BLM and ATR is associated with movement to DDI foci and recruitment of the p53 binding protein 53BP1 to the DDI foci (22,39). Thus, BLM is one of the earliest components to assoc...

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...ompromised by expression of kinase-defective ATR (Franchitto and Pichierri, 2002). More recently, it has been shown that ATR binds to human BLM and phosphorylates both threonine-99 and threonine-122 (=-=Davies et al., 2004-=-). Cells harboring a mutant of BLM that cannot be phosphorylated on these two sites display a defect in recovery from S phase arrest. Although many experiments have been performed on human BLM, its ex...