Small molecule inhibitors of PCNA/PIP-box interaction suppress translesion DNA synthesis

Actis, Marcelo L.; Inoue, Akira; Evison, Benjamin J.; Perry, Scott; Punchihewa, Chandanamali; Fujii, Naoaki

doi:10.1016/j.bmc.2013.01.022

Cited by 36 publications

(55 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our proposed model for p15-modulated PCNA sliding along the DNA could in future be validated by single-molecule experiments 40 . The PIP-box/PCNA interaction is a promising target for cancer therapeutics 43,44 . Yet, PCNA directs fundamental DNAtemplated processes, and targeting its common interaction site for so many different PIP-box proteins might cause unspecific cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Structure of p15PAF–PCNA complex and implications for clamp sliding during DNA replication and repair

et al. 2015

View full text Add to dashboard Cite

The intrinsically disordered protein p15 PAF regulates DNA replication and repair by binding to the proliferating cell nuclear antigen (PCNA) sliding clamp. We present the structure of the human p15 PAF -PCNA complex. Crystallography and NMR show the central PCNA-interacting protein motif (PIP-box) of p15 PAF tightly bound to the front-face of PCNA. In contrast to other PCNA-interacting proteins, p15 PAF also contacts the inside of, and passes through, the PCNA ring. The disordered p15 PAF termini emerge at opposite faces of the ring, but remain protected from 20S proteasomal degradation. Both free and PCNA-bound p15 PAF binds DNA mainly through its histone-like N-terminal tail, while PCNA does not, and a model of the ternary complex with DNA inside the PCNA ring is consistent with electron micrographs. We propose that p15 PAF acts as a flexible drag that regulates PCNA sliding along the DNA and facilitates the switch from replicative to translesion synthesis polymerase binding.

show abstract

Section: Discussionmentioning

confidence: 99%

Structure of p15PAF–PCNA complex and implications for clamp sliding during DNA replication and repair

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Previously, we found that PCNA/PIP-box interaction inhibitors inhibit TLS assayed by reactivation of pGL plasmid that was nonspecifically damaged by cisplatin in NER-null cells (8). Most of the DNA damage by cisplatin consists of base monoalkylations or intrastrand cross-links.…”

Section: Discussionmentioning

confidence: 99%

“…We (5,8) and other groups (47) have shown that PCNA is a possible drug target for chemosensitization by interfering with its numerous functions for DNA damage response. One of the characteristic features of PCNA is that it is homotrimeric on DNA, and each monomer has at least three functional sites and residues as follows: the PIP-box cavity, Lys-164, and Lys127 (4).…”

Section: Discussionmentioning

confidence: 99%

“…Chemical Synthesis-Preparation of all PCNA/PIP-box interaction inhibitors has been described previously (5,8) except for compound 6, which is described below. A mixture of 4-(2-aminoethyl)phenol (200 mg, 1.46 mmol) in dioxane (3 ml) and water (3 ml) was adjusted to pH ϳ10.…”

Section: Methodsmentioning

confidence: 99%

“…A plasmid reactivation assay with a reporter plasmid containing an SV40 origin and nonspecific cisplatin adducts measures NER activity when assayed in cells lacking SV40 large T antigen and TLS activity when assayed in cells expressing T antigen but deficient in NER. Using this assay, we previously found that T2AA inhibited TLS but not NER (5,8). The more chemotherapeutically crucial cisplatininduced DNA lesion is the ICL.…”

Section: T2aa Binds To Pcna At the Pip-box Cavity And Adjacent Tomentioning

confidence: 99%

See 2 more Smart Citations

A Small Molecule Inhibitor of Monoubiquitinated Proliferating Cell Nuclear Antigen (PCNA) Inhibits Repair of Interstrand DNA Cross-link, Enhances DNA Double Strand Break, and Sensitizes Cancer Cells to Cisplatin

Inoue

Kikuchi

Hishiki

et al. 2014

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background: Lys-164-monoubiquitinated PCNA is essential for interstrand DNA cross-link (ICL) repair. Results: A small molecule, T2AA, bi-molecularly binds to PCNA at a PIP-box cavity and close to Lys-164. T2AA inhibited monoubiquitinated PCNA interactions and ICL repair and enhanced DNA double strand breaks. Conclusion: An inhibitor of monoubiquitinated PCNA inhibits ICL repair. Significance: Inhibition of monoubiquitinated PCNA could improve chemotherapeutic efficacy.

show abstract

Targeting PCNA with Peptide Mimetics for Therapeutic Purposes

2019

View full text Add to dashboard Cite

Proliferating cell nuclear antigen (PCNA) is an excellent inhibition target to shut down highly proliferative cells and thereby develop a broad‐spectrum cancer therapeutic. It interacts with a wide variety of proteins through a conserved motif referred to as the PCNA‐interacting protein (PIP) box. There is large sequence diversity between high‐affinity PCNA binding partners, but with conservation of the binding structure—a well‐defined 310‐helix. Herein, all current PIP‐box peptides crystallised with human PCNA are collated to reveal common trends between binding structure and affinity. Key intra‐ and intermolecular hydrogen‐bonding networks that stabilise the 310‐helix of PIP‐box partners are highlighted and related back to the canonical PIP‐box motif. High correlation with the canonical PIP‐box sequence does not directly afford high affinity. Instead, we summarise key interactions that stabilise the binding structure that leads to enhanced PCNA binding affinity. These interactions also implicate the “non‐conserved” residues within the PIP‐box that have previously been overlooked. Such insights will allow a more directed approach to develop therapeutic PCNA inhibitors.

show abstract

Small molecule inhibitors of PCNA/PIP-box interaction suppress translesion DNA synthesis

Cited by 36 publications

References 37 publications

Structure of p15PAF–PCNA complex and implications for clamp sliding during DNA replication and repair

Structure of p15PAF–PCNA complex and implications for clamp sliding during DNA replication and repair

A Small Molecule Inhibitor of Monoubiquitinated Proliferating Cell Nuclear Antigen (PCNA) Inhibits Repair of Interstrand DNA Cross-link, Enhances DNA Double Strand Break, and Sensitizes Cancer Cells to Cisplatin

Targeting PCNA with Peptide Mimetics for Therapeutic Purposes

Contact Info

Product

Resources

About