Structural basis for cisplatin DNA damage tolerance by human polymerase η during cancer chemotherapy.

Nature Structural & Molecular Biology
Ajay UmmatAneel K Aggarwal

Abstract

A major clinical problem in the use of cisplatin to treat cancers is tumor resistance. DNA polymerase η (Pol-η) is a crucial polymerase that allows cancer cells to cope with the cisplatin-DNA adducts that are formed during chemotherapy. We present here a structure of human Pol-η inserting deoxycytidine triphosphate (dCTP) opposite a cisplatin intrastrand cross-link (PtGpG). We show that the specificity of human Pol-η for PtGpG derives from an active site that is open to permit Watson-Crick geometry of the nascent PtGpG-dCTP base pair and to accommodate the lesion without steric hindrance. This specificity is augmented by the residues Gln38 and Ser62, which interact with PtGpG, and Arg61, which interacts with the incoming dCTP. Collectively, the structure provides a basis for understanding how Pol-η in human cells can tolerate the DNA damage caused by cisplatin chemotherapy and offers a framework for the design of inhibitors in cancer therapy.

References

Jun 19, 2001·Mutation Research·M Kartalou, J M Essigmann
Dec 31, 2003·Methods in Enzymology·Martyn D WinnMiroslav Z Papiz
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Mar 25, 2005·Nature Reviews. Drug Discovery·Dong Wang, Stephen J Lippard
Apr 5, 2005·Acta Crystallographica. Section D, Biological Crystallography·Airlie J McCoyRandy J Read
Jun 15, 2005·Annual Review of Biochemistry·Satya PrakashLouise Prakash
Oct 1, 2005·Science·Deepak T NairAneel K Aggarwal
Nov 4, 2005·Cancer Research·Mark R AlbertellaMark J O'Connor
Apr 11, 2006·Molecular Cancer Research : MCR·Yih-wen ChenKai-ming Chou
Apr 25, 2007·Nucleic Acids Research·Ian W DavisDavid C Richardson
Jul 13, 2007·Nature Reviews. Cancer·Lloyd Kelland
Feb 4, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Paolo CeppiGiorgio Scagliotti
Jun 26, 2010·Nature·Timothy D SilversteinAneel K Aggarwal
Jun 26, 2010·Nature·Christian BiertümpfelWei Yang
Jan 20, 2012·Nature·Christopher J Lord, Alan Ashworth

❮ Previous
Next ❯

Citations

May 1, 2013·Proceedings of the National Academy of Sciences of the United States of America·Ye ZhaoWei Yang
Nov 13, 2015·Journal of Chemical Information and Modeling·Melek N Ucisik, Sharon Hammes-Schiffer
Mar 19, 2013·Mutation Research·Samuel C SuarezScott D McCulloch
Oct 23, 2015·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Jinhong WangBai Kang
May 18, 2016·The Journal of Clinical Investigation·Qian WangLei Shi
Jul 1, 2016·Journal of Medicinal Chemistry·Dmitry M Korzhnev, M Kyle Hadden
Feb 23, 2017·ACS Applied Materials & Interfaces·Weiqi Zhang, Ching-Hsuan Tung
Dec 22, 2016·Chemical Communications : Chem Comm·Weiqi ZhangChing-Hsuan Tung
Apr 24, 2018·Cell Cycle·Yang YangCyrus Vaziri
Feb 3, 2019·The Biochemical Journal·Hala Ouzon-ShubeitaSeongmin Lee
Feb 11, 2020·The Biochemical Journal·Hala Ouzon-ShubeitaSeongmin Lee
Aug 6, 2013·Environmental and Molecular Mutagenesis·Renee A BeardsleeScott D McCulloch
Jul 15, 2015·IUBMB Life·Deepak T NairRahul Sharma
Dec 12, 2018·Current Genetics·Narottam AcharyaPremlata Kumari
Jun 14, 2019·Cell Death & Disease·Luciana Rodrigues GomesCarlos Frederico Martins Menck
Aug 21, 2019·Critical Reviews in Biochemistry and Molecular Biology·David Gallo, Grant W Brown
May 16, 2014·Dalton Transactions : an International Journal of Inorganic Chemistry·Ewelina LipiecJacinto Sá
Jul 10, 2018·Scientific Reports·Elizaveta O BoldinovaAlena V Makarova
Aug 8, 2019·Angewandte Chemie·Tiantian WuBaoquan Ding
Oct 28, 2019·Mutagenesis·Roberto Silvestri, Stefano Landi
Oct 14, 2020·Biochemistry. Biokhimii︠a︡·E S ShilkinA V Makarova
Jun 3, 2021·Cells·Stijn WenmaekersRichard P Meijer
Apr 21, 2017·The Journal of Physical Chemistry. B·Melek N Ucisik, Sharon Hammes-Schiffer

❮ Previous
Next ❯

Methods Mentioned

BETA
PCR

Software Mentioned

COOT
REFMAC
MolProbity
IMAGEQUANT

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.