Involvement of mammalian Mus81 in genome integrity and tumor suppression.
Mus81-Eme1 endonuclease has been implicated in the rescue of stalled replication forks and the resolution of meiotic recombination intermediates in yeast. We used gene targeting to study the physiological requirements of Mus81 in mammals. Mus81-/- mice are viable and fertile, which indicates that mammalian Mus81 is not essential for recombination processes associated with meiosis. Mus81-deficient mice and cells were hypersensitive to the DNA cross-linking agent mitomycin C but not to gamma-irradiation. Remarkably, both homozygous Mus81-/- and heterozygous Mus81+/- mice exhibited a similar susceptibility to spontaneous chromosomal damage and a profound and equivalent predisposition to lymphomas and other cancers. These studies demonstrate a critical role for the proper biallelic expression of the mammalian Mus81 in the maintenance of genomic integrity and tumor suppression.
McPherson
John Peter
JP
Ontario Cancer Institute, 620 University Avenue, Suite 706, Toronto, Ontario, Canada M5G 2C1.
Lemmers
Bénédicte
B
Chahwan
Richard
R
Pamidi
Ashwin
A
Migon
Eva
E
Matysiak-Zablocki
Elzbieta
E
Moynahan
Mary Ellen
ME
Essers
Jeroen
J
Hanada
Katsuhiro
K
Poonepalli
Anuradha
A
Sanchez-Sweatman
Otto
O
Khokha
Rama
R
Kanaar
Roland
R
Jasin
Maria
M
Hande
M Prakash
MP
Hakem
Razqallah
R
D000483:Alleles; D000818:Animals; D002869:Chromosome Aberrations; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D004622:Embryo, Mammalian / Q000166:cytology; D005314:Embryonic and Fetal Development; D004720:Endonucleases; D005720:Gamma Rays; D018390:Gene Targeting; D020022:Genetic Predisposition to Disease; D016678:Genome; D042822:Genomic Instability; D006579:Heterozygote; D008223:Lymphoma / Q000209:etiology / Q000235:genetics / Q000473:pathology; D008540:Meiosis; D051379:Mice; D016685:Mitomycin / Q000494:pharmacology; D009369:Neoplasms / Q000209:etiology / Q000235:genetics*; D011995:Recombination, Genetic; D029701:Saccharomyces cerevisiae Proteins; D012854:Sister Chromatid Exchange; D013234:Stem Cells; D013601:T-Lymphocytes / Q000502:physiology
D004268:DNA-Binding Proteins; D029701:Saccharomyces cerevisiae Proteins; D016685:Mitomycin; D004720:Endonucleases; C411624:MUS81 protein, S cerevisiae; C498773:Mus81 protein, mouse