Collaboration of Werner syndrome protein and BRCA1 in cellular responses to DNA interstrand cross-links.
Cells deficient in the Werner syndrome protein (WRN) or BRCA1 are hypersensitive to DNA interstrand cross-links (ICLs), whose repair requires nucleotide excision repair (NER) and homologous recombination (HR). However, the roles of WRN and BRCA1 in the repair of DNA ICLs are not understood and the molecular mechanisms of ICL repair at the processing stage have not yet been established. This study demonstrates that WRN helicase activity, but not exonuclease activity, is required to process DNA ICLs in cells and that WRN cooperates with BRCA1 in the cellular response to DNA ICLs. BRCA1 interacts directly with WRN and stimulates WRN helicase and exonuclease activities in vitro. The interaction between WRN and BRCA1 increases in cells treated with DNA cross-linking agents. WRN binding to BRCA1 was mapped to BRCA1 452-1079 amino acids. The BRCA1/BARD1 complex also associates with WRN in vivo and stimulates WRN helicase activity on forked and Holliday junction substrates. These findings suggest that WRN and BRCA1 act in a coordinated manner to facilitate repair of DNA ICLs.
Cheng
Wen-Hsing
WH
Laboratory of Molecular Gerontology, National Institute on Aging, NIH, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
Kusumoto
Rika
R
Opresko
Patricia L
PL
Sui
XiuFen
X
Huang
Shurong
S
Nicolette
Matthew L
ML
Paull
Tanya T
TT
Campisi
Judith
J
Seidman
Michael
M
Bohr
Vilhelm A
VA
D019313:BRCA1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003432:Cross-Linking Reagents / Q000633:toxicity; D004249:DNA Damage; D004265:DNA Helicases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D004260:DNA Repair; D005090:Exodeoxyribonucleases; D005092:Exonucleases / Q000378:metabolism; D005363:Ficusin / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D034622:RNA Interference; D053484:RecQ Helicases; D000071657:Werner Syndrome Helicase
D019313:BRCA1 Protein; D003432:Cross-Linking Reagents; D005090:Exodeoxyribonucleases; D005092:Exonucleases; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase; D005363:Ficusin