| 1. |
- Lehmann, Laura C., et al.
(författare)
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Mechanistic Insights into Autoinhibition of the Oncogenic Chromatin Remodeler ALC1
- 2017
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Ingår i: Molecular Cell. - : Elsevier BV. - 1097-2765 .- 1097-4164. ; 68:5, s. 847-859 (e7)
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Tidskriftsartikel (refereegranskat)abstract
- Human ALC1 is an oncogene-encoded chromatin-remodeling enzyme required for DNA repair that possesses a poly(ADP-ribose) (PAR)-binding macro domain. Its engagement with PARylated PARP1 activates ALC1 at sites of DNA damage, but the underlying-mechanism remains unclear. Here, we establish a dual role for the macro domain in autoinhibition of ALC1 ATPase activity and coupling to nucleosome mobilization. In the absence of DNA damage, an inactive conformation of the ATPase is maintained by juxtaposition of the macro domain against predominantly the C-terminal ATPase lobe through conserved electrostatic interactions. Mutations within this interface displace the macro domain, constitutively activate the ALC1 ATPase independent of PARylated PARP1, and alter the dynamics of ALC1 recruitment at DNA damage sites. Upon DNA damage, binding of PARylated PARP1 by the macro domain induces a conformational change that relieves autoinhibitory interactions with the ATPase motor, which selectively activates ALC1 remodeling upon recruitment to sites of DNA damage.
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| 2. |
- Lönn, Peter, et al.
(författare)
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PARP-1 attenuates Smad-mediated transcription
- 2010
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Ingår i: Molecular Cell. - : Elsevier BV. - 1097-2765 .- 1097-4164. ; 40:4, s. 521-532
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Tidskriftsartikel (refereegranskat)abstract
- The versatile cytokine transforming growth factor β (TGF-β) regulates cellular growth, differentiation, and migration during embryonic development and adult tissue homeostasis. Activation of TGF-β receptors leads to phosphorylation of Smad2 and Smad3, which oligomerize with Smad4 and accumulate in the nucleus where they recognize gene regulatory regions and orchestrate transcription. Termination of Smad-activated transcription involves Smad dephosphorylation, nuclear export, or ubiquitin-mediated degradation. In an unbiased proteomic screen, we identified poly(ADP-ribose) polymerase-1 (PARP-1) as a Smad-interacting partner. PARP-1 dissociates Smad complexes from DNA by ADP-ribosylating Smad3 and Smad4, which attenuates Smad-specific gene responses and TGF-β-induced epithelial-mesenchymal transition. Thus, our results identify ADP-ribosylation of Smad proteins by PARP-1 as a key step in controlling the strength and duration of Smad-mediated transcription.
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| 3. |
- Moustakas, Aristidis, et al.
(författare)
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Coordination of TGF-beta Signaling by Ubiquitylation
- 2013
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Ingår i: Molecular Cell. - : Elsevier BV. - 1097-2765 .- 1097-4164. ; 51:5, s. 555-556
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- In this issue, Zhang et al. (2013) demonstrate that the ubiquitin ligase TRAF4 associates with the TGF-β receptors, rescuing them from degradation and ubiquitylating TAK1 to activate non-Smad signaling, which together promote metastasis of breast cancer cells.
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