title: ATM protein-dependent phosphorylation of Rad50 protein regulates DNA repair and cell cycle control.
abstract: The Mre11/Rad50/NBN complex plays a central role in coordinating the cellular response to DNA double-strand breaks. The importance of Rad50 in that response is evident from the recent description of a patient with Rad50 deficiency characterized by chromosomal instability and defective ATM-dependent signaling. We report here that ATM (defective in ataxia-telangiectasia) phosphorylates Rad50 at a single site (Ser-635) that plays an important adaptor role in signaling for cell cycle control and DNA repair. Although a Rad50 phosphosite-specific mutant (S635G) supported normal activation of ATM in Rad50-deficient cells, it was defective in correcting DNA damage-induced signaling through the ATM-dependent substrate SMC1. This mutant also failed to correct radiosensitivity, DNA double-strand break repair, and an S-phase checkpoint defect in Rad50-deficient cells. This was not due to disruption of the Mre11/Rad50/NBN complex revealing for the first time that phosphorylation of Rad50 plays a key regulatory role as an adaptor for specific ATM-dependent downstream signaling through SMC1 for DNA repair and cell cycle checkpoint control in the maintenance of genome integrity.
authors.affiliation: Radiation Biology and Oncology Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland 4029, Australia.
authors.forename: Magtouf
authors.initials: M
authors.lastname: Gatei
authors.forename: Burkhard
authors.initials: B
authors.lastname: Jakob
authors.forename: Philip
authors.initials: P
authors.lastname: Chen
authors.forename: Amanda W
authors.initials: AW
authors.lastname: Kijas
authors.forename: Olivier J
authors.initials: OJ
authors.lastname: Becherel
authors.forename: Nuri
authors.initials: N
authors.lastname: Gueven
authors.forename: Geoff
authors.initials: G
authors.lastname: Birrell
authors.forename: Ji-Hoon
authors.initials: JH
authors.lastname: Lee
authors.forename: Tanya T
authors.initials: TT
authors.lastname: Paull
authors.forename: Yaniv
authors.initials: Y
authors.lastname: Lerenthal
authors.forename: Shazrul
authors.initials: S
authors.lastname: Fazry
authors.forename: Gisela
authors.initials: G
authors.lastname: Taucher-Scholz
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kalb
authors.forename: Detlev
authors.initials: D
authors.lastname: Schindler
authors.forename: Regina
authors.initials: R
authors.lastname: Waltes
authors.forename: Thilo
authors.initials: T
authors.lastname: Dörk
authors.forename: Martin F
authors.initials: MF
authors.lastname: Lavin
mesh_terms: D017766:Acid Anhydride Hydrolases; D048868:Adaptor Proteins, Signal Transducing; D001260:Ataxia Telangiectasia / Q000473:pathology; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism* / Q000502:physiology*; D002868:Chromosomal Proteins, Non-Histone / Q000502:physiology*; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000172:deficiency / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D042822:Genomic Instability; D006801:Humans; D050505:Mutant Proteins; D010766:Phosphorylation / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011836:Radiation Tolerance; D016196:S Phase; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000098550:Structural Maintenance of Chromosome Protein 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D050505:Mutant Proteins; D025521:Tumor Suppressor Proteins; D000098550:Structural Maintenance of Chromosome Protein 1; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes