A small molecule directly inhibits the p53 transactivation domain from binding to replication protein A

Glanzer, Jason G.; Carnes, Katie A.; Soto, Patricia; Liu, Shengqin; Parkhurst, Lawrence J.; Oakley, Gregory G.

doi:10.1093/nar/gks1291

Back to Previous Page

- Add this to...
- Twitter
- Facebook
- Google Bookmarks
- LinkedIn

A small molecule directly inhibits the p53 transactivation domain from binding to replication protein A

Published Date:

Dec 24 2012

Publisher's site:

http://dx.doi.org/10.1093/nar/gks1291 New Site Icon

Source:

Nucleic Acids Res. 2012; 41(3):2047-2059.

[PDF-2.14 MB]

Details:

Personal Authors:

Glanzer, Jason G. ; Carnes, Katie A. ; Soto, Patricia ; Liu, Shengqin ; Parkhurst, Lawrence J. ; ... More ▼

Keywords:

[+]

Pubmed ID:

23267009

Pubmed Central ID:

PMC3561959

Description:

Replication protein A (RPA), essential for DNA replication, repair and DNA damage signalling, possesses six ssDNA-binding domains (DBDs), including DBD-F on the N-terminus of the largest subunit, RPA70. This domain functions as a binding site for p53 and other DNA damage and repair proteins that contain amphipathic alpha helical domains. Here, we demonstrate direct binding of both ssDNA and the transactivation domain 2 of p53 (p53TAD2) to DBD-F, as well as DBD-F-directed dsDNA strand separation by RPA, all of which are inhibited by fumaropimaric acid (FPA). FPA binds directly to RPA, resulting in a conformational shift as determined through quenching of intrinsic tryptophan fluorescence in full length RPA. Structural analogues of FPA provide insight on chemical properties that are required for inhibition. Finally, we confirm the inability of RPA possessing R41E and R43E mutations to bind to p53, destabilize dsDNA and quench tryptophan fluorescence by FPA, suggesting that protein binding, DNA modulation and inhibitor binding all occur within the same site on DBD-F. The disruption of p53-RPA interactions by FPA may disturb the regulatory functions of p53 and RPA, thereby inhibiting cellular pathways that control the cell cycle and maintain the integrity of the human genome.

Document Type:

Journal Article

Collection(s):

CDC Public Access

Funding:

GM59346/GM/NIGMS NIH HHS/United States
P20-RR01875/RR/NCRR NIH HHS/United States
P20RR018759/RR/NCRR NIH HHS/United States
RR015468/RR/NCRR NIH HHS/United States
RSG1003101CCG/CC/ODCDC CDC HHS/United States

Supporting Files:

	gks1291f4p.jpg	image/jpeg
	gks1291f5p.gif	image/gif
	gks1291f5p.jpg	image/jpeg
	gks1291f6p.gif	image/gif
	gks1291f6p.jpg	image/jpeg
	gks1291m1.gif	image/gif
	gks1291m1.jpg	image/jpeg
	gks1291m10.gif	image/gif
	gks1291m10.jpg	image/jpeg
	gks1291m11.gif	image/gif
	gks1291.nxml	text/plain
	gks1291m11.jpg	image/jpeg
	gks1291m2.gif	image/gif
	gks1291m2.jpg	image/jpeg
	gks1291m3.gif	image/gif
	gks1291m3.jpg	image/jpeg
	gks1291m4.gif	image/gif
	gks1291m4.jpg	image/jpeg
	gks1291m5.gif	image/gif
	gks1291m5.jpg	image/jpeg
	gks1291m6.gif	image/gif
	gks1291f1p.gif	image/gif
	gks1291m6.jpg	image/jpeg
	gks1291m7.gif	image/gif
	gks1291m7.jpg	image/jpeg
	gks1291m8.gif	image/gif
	gks1291m8.jpg	image/jpeg
	gks1291m9.gif	image/gif
	gks1291m9.jpg	image/jpeg
	license.txt	text/plain
	gks1291f1p.jpg	image/jpeg
	supp_41_3_2047__index.html	text/html
	supp_gks1291_nar-01910-m-2012-File003.docx	application/vnd.openxmlformats-officedocument.wordprocessingml.document
	supp_gks1291_nar-01910-m-2012-File004.pdf	application/pdf
	gks1291f2p.gif	image/gif
	gks1291f2p.jpg	image/jpeg
	gks1291f3p.gif	image/gif
	gks1291f3p.jpg	image/jpeg
	gks1291f4p.gif	image/gif

No Related Documents.

You May Also Like:

KSHV Reactivation and Novel Implications of Protein Isomerization on Lytic Switch Control

Personal Author:

Guito, Jonathan; Lukac, David M.;

Published:

Jan 12 2015

Source:

Viruses. 2015; 7(1):72-109.

Description:

In Kaposi's sarcoma-associated herpesvirus (KSHV) oncogenesis, both latency and reactivation are hypothesized to potentiate tumor growth. The KSHV Rta protein is the lytic switch for reactivation. Rta transactivates essential genes via interactions w...

File Type:

[PDF - 2.94 MB]
The latency-associated nuclear antigen, a multifunctional protein central to Kaposi’s sarcoma-associated herpesvirus latency

Personal Author:

Ballestas, Mary E; Kaye, Kenneth M;

Published:

Dec 2011

Source:

Future Microbiol. 2011; 6(12).

Description:

Latency-associated nuclear antigen (LANA) is encoded by the Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) open reading frame 73. LANA is expressed during latent KSHV infection of cells, including tumor cells, such as primary effusion lymph...

File Type:

[PDF - 1.15 MB]
Molecular Basis of Electrophilic and Oxidative Defense: Promises and Perils of Nrf2

Personal Author:

Ma, Qiang; He, Xiaoqing;

Published:

Sep 10 2012

Source:

Pharmacol Rev. 64(4):1055-1081.

Description:

Induction of drug-metabolizing enzymes through the antioxidant response element (ARE)-dependent transcription was initially implicated in chemoprevention against cancer by antioxidants. Recent progress in understanding the biology and mechanism of in...

File Type:

[PDF - 1.26 MB]
Role of Epithelial-Mesenchyme Transition in Chlamydia Pathogenesis

Personal Author:

Igietseme, Joseph U.; Omosun, Yusuf; Stuchlik, Olga; Reed, Matthew S.; Partin, James; He, Qing; Joseph, Kahaliah; Ellerson, Debra; Bollweg, Brigid; George, Zenas; Eko, Francis O.; Bandea, Claudiu; Liu, Hsi; Yang, Genyan; Shieh, Wun-Ju; Pohl, Jan; Karem, Kevin; Black, Carolyn M.;

Published:

Dec 17 2015

Source:

PLoS One. 10(12).

Description:

Chlamydia trachomatis genital infection in women causes serious adverse reproductive complications, and is a strong co-factor for human papilloma virus (HPV)-associated cervical epithelial carcinoma. We tested the hypothesis that Chlamydia induces ep...

File Type:

[PDF - 14.05 MB]
NanoScript: A Nanoparticle-Based Artificial Transcription Factor for Effective Gene Regulation

Personal Author:

Patel, Sahishnu; Jung, Dongju; Yin, Perry T.; Carlton, Peter; Yamamoto, Makoto; Bando, Toshikazu; Sugiyama, Hiroshi; Lee, Ki-Bum;

Published:

Aug 20 2014

Source:

ACS Nano. 2014; 8(9):8959-8967.

Description:

Transcription factor (TF) proteins are master regulators of transcriptional activity and gene expression. TF-based gene regulation is a promising approach for many biological applications; however, several limitations hinder the full potential of TFs...

File Type:

[PDF - 6.11 MB]