4Q8F: Human Dna Polymerase Eta Extending Primer Immediately After A Phenanthriplatin Adducted G

Citation:
Abstract
Platinum drugs are a mainstay of anticancer chemotherapy. Nevertheless, tumors often display inherent or acquired resistance to platinum-based treatments, prompting the search for new compounds that do not exhibit cross-resistance with current therapies. Phenanthriplatin, cis-diamminephenanthridinechloroplatinum(II), is a potent monofunctional platinum complex that displays a spectrum of activity distinct from those of the clinically approved platinum drugs. Inhibition of RNA polymerases by phenanthriplatin lesions has been implicated in its mechanism of action. The present study evaluates the ability of phenanthriplatin lesions to inhibit DNA replication, a function disrupted by traditional platinum drugs. Phenanthriplatin lesions effectively inhibit DNA polymerases nu, zeta, and kappa and the Klenow fragment. In contrast to results obtained with DNA damaged by cisplatin, all of these polymerases were capable of inserting a base opposite a phenanthriplatin lesion, but only Pol eta, an enzyme efficient in translesion synthesis, was able to fully bypass the adduct, albeit with low efficiency. X-ray structural characterization of Pol eta complexed with site-specifically platinated DNA at both the insertion and +1 extension steps reveals that phenanthriplatin on DNA interacts with and inhibits Pol eta in a manner distinct from that of cisplatin-DNA adducts. Unlike cisplatin and oxaliplatin, the efficacies of which are influenced by Pol eta expression, phenanthriplatin is highly toxic to both Pol eta+ and Pol eta- cells. Given that increased expression of Pol eta is a known mechanism by which cells resist cisplatin treatment, phenanthriplatin may be valuable in the treatment of cancers that are, or can easily become, resistant to cisplatin.
PDB ID: 4Q8FDownload
MMDB ID: 121236
PDB Deposition Date: 2014/4/26
Updated in MMDB: 2014/08
Experimental Method:
x-ray diffraction
Resolution: 2.8  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 4Q8F: trimeric; determined by author and by software (PISA)
Molecular Components in 4Q8F
Label Count Molecule
Protein (1 molecule)
1
DNA Polymerase ETA(Gene symbol: POLH)
Molecule annotation
Nucleotides(2 molecules)
1
5'-d(*cp*ap*tp*cp*gp*tp*cp*ap*cp*ap*cp*t)-3'
Molecule annotation
1
5'-d(*ap*gp*tp*gp*tp*gp*ap*c)-3'
Molecule annotation
Chemicals (7 molecules)
1
2
2
2
3
3
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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