2014
DOI: 10.18632/aging.100629
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Abstract: WRN protein, defective in Werner syndrome (WS), a human segmental progeria, is a target of serine/threonine kinases involved in sensing DNA damage. DNA-PK phosphorylates WRN in response to DNA double strand breaks (DSBs). However, the main phosphorylation sites and functional importance of the phosphorylation of WRN has remained unclear. Here, we identify Ser-440 and −467 in WRN as major phosphorylation sites mediated by DNA-PK. In vitro, DNA-PK fails to phosphorylate a GST-WRN fragment with S440A and/or S467A… Show more

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Cited by 21 publications
(29 citation statements)
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References 34 publications
(29 reference statements)
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“…It has been proposed that the choice between HR and NHEJ is determined in part by heterochromatin status and the chemical nature of the DSB, and that canonical NHEJ may be preferred for exogenous DSB repair during the G 0 and G 1 phases of the cell cycle (Kakarougkas and Jeggo, 2014; Keijzers et al, 2014). WRN physically interacts with a number of players in NHEJ such as Ku70/80, the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and DNA ligase IV/XRCC4 (Kusumoto-Matsuo et al, 2014; Kusumoto et al, 2008). The potential physiologic significance of WRN in NHEJ repair is suggested by the demonstration of extensive deletions of reporter plasmids, particularly at 3’ overhang ends, in cells lacking WRN protein (Oshima et al, 2002).…”
Section: Cellular Functions Of the Wrn Gene Productmentioning
confidence: 99%
“…But, considering these factors are also phosphorylated by ATM, the role of DNA-PKcs-mediated phosphorylation of these proteins is not exactly clear. However, it was recently found that phosphorylation of the implicated NHEJ factor Werner (WRN) by DNA-PKcs is required for efficient DSB repair, possibly identifying a DNA-PKcs mediated phosphorylation of a substrate that is important for NHEJ [66]. Furthermore, a number of new in vivo substrates of DNA-PKcs have emerged [65].…”
Section: Dna-pk Kinase Activitymentioning
confidence: 99%
“…As previously reviewed [21], DNAPKcs can phosphorylate a number of NHEJ proteins, including Ku, XRCC4, XLF, and Lig4; however, none of these phosphorylation events contribute to C-NHEJ transduction. The phosphorylation of the DNA nuclease WRN by DNA-PKcs was recently shown to play a crucial role in NHEJ DSB repair [34]. In parallel, DNA-PKcs can also be phosphorylated.…”
Section: The Processing Of Dsb Dna Endmentioning
confidence: 99%
“…WRN is an intriguing candidate for CDK-dependent regulation of the DNA2 branch of long-range end resection. Indeed, WRN undergoes multiple phosphorylation events in response to DNA damage or replication stress and associates with the MRE11 complex 19 20 21 22 . Moreover, loss of WRN markedly sensitizes cells to CPT, an agent that induces fork collapse resulting in DSBs in S-phase 23 24 .…”
mentioning
confidence: 99%
“…DSBs that require no resection (ligatable DNA ends) are repaired by Ku70/80 and XRCC4/Ligase IV/XLF, independent of DNA-PKcs (Mari et al , 2006; Reynolds et al , 2012). Extensive work on WRN in C-NHEJ, demonstrates that WRN physically and functionally interacts with several C-NHEJ repair proteins (Karmakar et al , 2002b; Kusumoto-Matsuo et al , 2010, 2014). Ku70/80 and Ligase IV/XRCC4 stimulate WRN exonuclease but not WRN helicase activity (Cooper et al , 2000; Kusumoto et al , 2008; Li & Comai, 2001), clear demonstrations of how protein interactions dictate specificity of enzyme activities.…”
Section: Canonical Nhejmentioning
confidence: 99%