Stable maintenance of the Mre11-Rad50-Nbs1 complex is sufficient to restore the DNA double-strand break response in cells lacking RecQL4 helicase activity

Abstract

Lee JK, Stable maintenance of the Mre11-Rad50-Nbs1 complex is sufficient to restore the DNA double-strand break response in cells lacking RecQL4 helicase activity,

Deubiquitinase USP2 stabilizes the MRE11–RAD50–NBS1 complex at DNA double-strand break sites by counteracting the ubiquitination of NBS1

“…We then examined whether USP2 influences DSB-dependent ubiquitination of NBS1 proteins. As shown in a previous study ( 24 ), ubiquitination of NBS1 was significantly increased by treatment with NCS, and this was reversed by USP2 overexpression to almost the same level as that in nondamaged cells ( Fig. 2 D ).…”

“…To explore the deubiquitinases that influence the stability of the MRN complex during the DSB response, we took advantage of RECQL4-depleted cells, in which the MRN complex is prematurely disassembled from DSB sites by ubiquitin-dependent degradation of the NBS1 protein ( 24 ). Several deubiquitinases that have been shown to be associated with DNA damage responses, cell cycle, or carcinogenesis were individually overexpressed in RECQL4-depleted cells, and MRE11 foci were examined after treating cells with neocarzinostatin (NCS), a DSB-inducing reagent.…”

“…Premature disassembly of the MRN complex from DSB sites has been shown to be caused by SKP2-dependent ubiquitination of the NBS1 protein in RECQL4-defective cells ( 24 ). To test the possibility that USP2 increases the stability of the MRN complex at DSB sites by counteracting the ubiquitination of NBS1, we examined the recruitment of USP2 to DSB sites.…”

“…Recently, premature disassembly of the MRN complex from DSB sites by SKP2-dependent ubiquitination of NBS1 was observed in cells lacking RECQL4 helicase activity and overexpression of a deubiquitinase, USP28, restored the stability of the MRN complex at DSB sites, ATM activation, and HR repair in these cells ( 24 ). As K48-linked ubiquitination of NBS1 by SKP2 E3 ligase also occurs in cells with intact RECQL4 helicase and overexpression of USP28 reduces the ubiquitination of NBS1, these results suggest that there may be a novel control mechanism that plays an important role in the DSB response by ubiquitination and deubiquitination of NBS1.…”

Non-Melanoma Skin Cancers and Other Cutaneous Manifestations in Bone Marrow Failure Syndromes and Rare DNA Repair Disorders

“…RECQL4 is a DNA helicase in the same family as WRN and BLM ( 96 ). REQL4 appears to be involved in double stranded DNA repair through stabilization of the Mre11-Rad50-Nbs1 complex; absence of functional RECQL led to premature degradation of the MRN complex in vitro ( 97 ). APC1 is a ubiquitin ligase and the protein coded for by ANAPC1.…”