Overall structure of human PrimPol ternary complex with template-primer DNA and incoming dATP. The N-helix and modules ModN and ModC are shown in cartoon representation in dark blue, yellow, and cyan, respectively. The DNA is shown as gray sticks, and the Ca2+ ion is shown as a light blue sphere. The templating base T and the incoming dATP are shown in red. Yellow and cyan dashed lines depict unstructured regions in the ModN and ModC, respectively. The side chains of key catalytic active-site residues Asp114, Glu116, and Asp280 are highlighted in red. Secondary structure elements (α helices and β strands) are labeled in black.
A research team led by scientists at the Icahn School of Medicine at Mount Sinai (ISMMS) has solved the 3D structure of a key protein that helps damaged cellular DNA repair itself. Knowing the chemical structure of the protein will likely help drug designers build novel anti-cancer agents. The study involved a team from multiple institutions, working for >2 years to decipher the unusual configuration of the protein PrimPol, whose function was discovered in 2013. PrimPol is used in cells when normal repair proteins encounter damaged sections of DNA, often caused by chemotherapy drugs. The protein can skip over the damage to rescue DNA replication, says Prof. Aggarwal, PhD. “PrimPol can counter the anti-cancer action of common chemotherapeutic agents such as cisplatin. By inhibiting PrimPol, we believe that we can increase the efficacy of chemotherapeutic agents in the treatment of many cancers,” he says.
DNA damage happens constantly – more than 100,000 events occur in every human cell each day. PrimPol is necessary for the cell to repair DNA damage, but sometimes this may not be to the individual’s benefit, as in the case of resistance to chemotherapeutic agents, says the study’s Olga Rechkoblit, PhD, Assistant Professor of Pharmacological Sciences at ISMMS.
The basic steps involved in DNA replication are known. The first step involves unzipping the intertwined double helix DNA structure, creating a “Y” shape replication fork. These two strands act as templates for making the new DNA strands. A short piece of RNA, ie primer (produced by a primase enzyme) acts as the starting point for the synthesis of new DNA. “It had been believed that DNA polymerase and primase activities in human cells were the province of separate enzymes. Then PrimPol was discovered, and the understanding of DNA replication changed dramatically. PrimPol was found to be capable of both restarting and performing DNA synthesis after DNA replication stalls,” says Dr. Rechkoblit.
While scientists were excited by the discovery of the enzyme, they didn’t understand how it worked. “Many chemotherapy agents kill cancer cells by damaging their DNA and preventing the completion of DNA replication. PrimPol, on the other hand, promotes the replication progression and, thus, cell survival,” she says. “Knowing the structure of PrimPol described in the current study is invaluable for designing an inhibitor for this enzyme as a future cancer therapy.”
“The idea would be that a patient could be given a PrimPol inhibitor – an agent that shuts down this clever machine – at the same time as chemotherapy, so that cancer cells cannot repair the killing damage chemotherapy offers,” she says. https://www.eurekalert.org/pub_releases/2016-10/tmsh-sok102416.php http://advances.sciencemag.org/content/2/10/e1601317.figures-only
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