Linkage between Werner syndrome protein and the Mre11 complex via Nbs1.
The Werner syndrome and the Nijmegen breakage syndrome are recessive genetic disorders that show increased genomic instability, cancer predisposition, hypersensitivity to mitomycin C and gamma-irradiation, shortened telomeres, and cell cycle defects. The protein mutated in the premature aging disease known as the Werner syndrome is designated WRN and is a member of the RecQ helicase family. The Nbs1 protein is mutated in Nijmegen breakage syndrome individuals and is part of the mammalian Mre11 complex together with the Mre11 and Rad50 proteins. Here, we show that WRN associates with the Mre11 complex via binding to Nbs1 in vitro and in vivo. In response to gamma-irradiation or mitomycin C, WRN leaves the nucleoli and co-localizes with the Mre11 complex in the nucleoplasm. We detect an increased association between WRN and the Mre11 complex after cellular exposure to gamma-irradiation. Small interfering RNA and complementation experiments demonstrated convergence of WRN and Nbs1 in response to gamma-irradiation or mitomycin C. Nbs1 is required for the Mre11 complex promotion of WRN helicase activity. Taken together, these results demonstrate a functional link between the two genetic diseases with partially overlapping phenotypes in a pathway that responds to DNA double strand breaks and interstrand cross-links.
Cheng
Wen-Hsing
WH
Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
von Kobbe
Cayetano
C
Opresko
Patricia L
PL
Arthur
L Matthew
LM
Komatsu
Kenshi
K
Seidman
Michael M
MM
Carney
James P
JP
Bohr
Vilhelm A
VA
D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D002460:Cell Line; D004265:DNA Helicases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005090:Exodeoxyribonucleases; D005720:Gamma Rays; D006367:HeLa Cells; D006801:Humans; D000076228:MRE11 Homologue Protein; D016685:Mitomycin / Q000494:pharmacology; D009687:Nuclear Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D053484:RecQ Helicases; D011994:Recombinant Proteins / Q000378:metabolism; D012016:Reference Values; D014162:Transfection; D000071657:Werner Syndrome Helicase
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016685:Mitomycin; D005090:Exodeoxyribonucleases; D000076228:MRE11 Homologue Protein; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase