The leukemia-associated Rho guanine nucleotide exchange factor LARG is required for efficient replication stress signaling
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作者:
Beveridge, Ryan D.
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Univ Sheffield, Sch Med, Acad Unit Mol Oncol, Genome Stabil Grp,Dept Oncol, Sheffield, S Yorkshire, EnglandUniv Sheffield, Sch Med, Acad Unit Mol Oncol, Genome Stabil Grp,Dept Oncol, Sheffield, S Yorkshire, England
Beveridge, Ryan D.
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Staples, Christopher J.
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Univ Sheffield, Sch Med, Acad Unit Mol Oncol, Genome Stabil Grp,Dept Oncol, Sheffield, S Yorkshire, EnglandUniv Sheffield, Sch Med, Acad Unit Mol Oncol, Genome Stabil Grp,Dept Oncol, Sheffield, S Yorkshire, England
Staples, Christopher J.
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Patil, Abhijit A.
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Univ Sheffield, Sch Med, Acad Unit Mol Oncol, Genome Stabil Grp,Dept Oncol, Sheffield, S Yorkshire, EnglandUniv Sheffield, Sch Med, Acad Unit Mol Oncol, Genome Stabil Grp,Dept Oncol, Sheffield, S Yorkshire, England
Patil, Abhijit A.
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Myers, Katie N.
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Univ Sheffield, Sch Med, Acad Unit Mol Oncol, Genome Stabil Grp,Dept Oncol, Sheffield, S Yorkshire, EnglandUniv Sheffield, Sch Med, Acad Unit Mol Oncol, Genome Stabil Grp,Dept Oncol, Sheffield, S Yorkshire, England
Myers, Katie N.
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Maslen, Sarah
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MRC, Mol Biol Lab, Div Cell Biol, Mass Spectrometry Grp, Cambridge CB2 2QH, EnglandUniv Sheffield, Sch Med, Acad Unit Mol Oncol, Genome Stabil Grp,Dept Oncol, Sheffield, S Yorkshire, England
Maslen, Sarah
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Skehel, J. Mark
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MRC, Mol Biol Lab, Div Cell Biol, Mass Spectrometry Grp, Cambridge CB2 2QH, EnglandUniv Sheffield, Sch Med, Acad Unit Mol Oncol, Genome Stabil Grp,Dept Oncol, Sheffield, S Yorkshire, England
Skehel, J. Mark
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Boulton, Simon J.
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London Res Inst, DNA CR UK Damage Response Lab, Clare Hall Labs, S Mimms, Herts, EnglandUniv Sheffield, Sch Med, Acad Unit Mol Oncol, Genome Stabil Grp,Dept Oncol, Sheffield, S Yorkshire, England
Boulton, Simon J.
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Collis, Spencer J.
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Univ Sheffield, Sch Med, Acad Unit Mol Oncol, Genome Stabil Grp,Dept Oncol, Sheffield, S Yorkshire, EnglandUniv Sheffield, Sch Med, Acad Unit Mol Oncol, Genome Stabil Grp,Dept Oncol, Sheffield, S Yorkshire, England
Collis, Spencer J.
[1
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[1] Univ Sheffield, Sch Med, Acad Unit Mol Oncol, Genome Stabil Grp,Dept Oncol, Sheffield, S Yorkshire, England
[2] MRC, Mol Biol Lab, Div Cell Biol, Mass Spectrometry Grp, Cambridge CB2 2QH, England
[3] London Res Inst, DNA CR UK Damage Response Lab, Clare Hall Labs, S Mimms, Herts, England
We previously identified and characterized TELO2 as a human protein that facilitates efficient DNA damage response (DDR) signaling. A subsequent yeast 2-hybrid screen identified LARG; Leukemia-Associated Rho Guanine Nucleotide Exchange Factor (also known as Arhgef12), as a potential novel TELO2 interactor. LARG was previously shown to interact with Pericentrin (PCNT), which, like TELO2, is required for efficient replication stress signaling. Here we confirm interactions between LARG, TELO2 and PCNT and show that a sub-set of LARG co-localizes with PCNT at the centrosome. LARG-deficient cells exhibit replication stress signaling defects as evidenced by; supernumerary centrosomes, reduced replication stress-induced H2AX and RPA nuclear foci formation, and reduced activation of the replication stress signaling effector kinase Chk1 in response to hydroxyurea. As such, LARG-deficient cells are sensitive to replication stress-inducing agents such as hydroxyurea and mitomycin C. Conversely we also show that depletion of TELO2 and the replication stress signaling kinase ATR leads to RhoA signaling defects. These data therefore reveal a level of crosstalk between the RhoA and DDR signaling pathways. Given that mutations in both ATR and PCNT can give rise to the related primordial dwarfism disorders of Seckel Syndrome and Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) respectively, which both exhibit defects in ATR-dependent checkpoint signaling, these data also raise the possibility that mutations in LARG or disruption to RhoA signaling may be contributory factors to the etiology of a sub-set of primordial dwarfism disorders.
机构:
Thomas Jefferson Univ, Dept Biochem & Mol Biol, Philadelphia, PA 19107 USAThomas Jefferson Univ, Dept Biochem & Mol Biol, Philadelphia, PA 19107 USA