Role of the Exocyst Complex Component Sec6/8 in Genomic Stability.
The exocyst is a heterooctomeric complex well appreciated for its role in the dynamic assembly of specialized membrane domains. Accumulating evidence indicates that this macromolecular machine also serves as a physical platform that coordinates regulatory cascades supporting biological systems such as host defense signaling, cell fate, and energy homeostasis. The isolation of multiple components of the DNA damage response (DDR) as exocyst-interacting proteins, together with the identification of Sec8 as a suppressor of the p53 response, suggested functional interactions between the exocyst and the DDR. We found that exocyst perturbation resulted in resistance to ionizing radiation (IR) and accelerated resolution of DNA damage. This occurred at the expense of genomic integrity, as enhanced recombination frequencies correlated with the accumulation of aberrant chromatid exchanges. Sec8 perturbation resulted in the accumulation of ATF2 and RNF20 and the promiscuous accumulation of DDR-associated chromatin marks and Rad51 repairosomes. Thus, the exocyst supports DNA repair fidelity by limiting the formation of repair chromatin in the absence of DNA damage.
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Michael J
MJ
Torres
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, USA The Houston Methodist Research Institute, Houston, Texas, USA.
Raj K
RK
Pandita
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Ozlem
O
Kulak
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Rakesh
R
Kumar
Hybrigenics, Inc., Paris, France.
Etienne
E
Formstecher
The Houston Methodist Research Institute, Houston, Texas, USA.
Nobuo
N
Horikoshi
The Houston Methodist Research Institute, Houston, Texas, USA.
Kalpana
K
Mujoo
The Houston Methodist Research Institute, Houston, Texas, USA.
Clayton R
CR
Hunt
Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, USA.
Yingming
Y
Zhao
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Lawrence
L
Lum
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Aubhishek
A
Zaman
Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa, USA.
Charles
C
Yeaman
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA Michael.White@UTSouthwestern.edu tpandita@houstonmethodist.org.
Michael A
MA
White
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, USA The Houston Methodist Research Institute, Houston, Texas, USA Michael.White@UTSouthwestern.edu tpandita@houstonmethodist.org.
Tej K
TK
Pandita
D051698:Activating Transcription Factor 2 / Q000032:analysis / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000032:analysis / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1; D045744:Cell Line, Tumor; D004260:DNA Repair; D005089:Exocytosis; D017353:Gene Deletion; D042822:Genomic Instability; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1; D044767:Ubiquitin-Protein Ligases / Q000032:analysis / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000032:analysis / Q000378:metabolism*
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C490685:EXOC3 protein, human; C489607:EXOC4 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D033921:Vesicular Transport Proteins; C506646:RNF20 protein, human; D044767:Ubiquitin-Protein Ligases