Study paves way for a new approach to fight infections

New Delhi (India Science Wire): A new way of handling diseases could soon be in the
offing with a team of researchers gaining new insights into the molecular mechanism of
living organisms.
Proliferating cell nuclear antigen (PCNA) is a protein that plays a significant role in DNA
replication, repair, and recombination processes of all organisms. Recruitment of DNA
polymerases by PCNA is an essential step during DNA replication and blocking this step by
targeting PCNA by any means can help tackle infections.
Since PCNA is a structural protein, it is widely accepted as a therapeutic target. Interestingly,
its structure looks similar across species, though a PCNA of a given species is rarely
functional in another. The new study has resolved this problem.
The researchers began by elucidating the X-ray crystal structure of the PCNA of a type of red
bread mold called Neurospora crassa and compared its structure–function relationship with
other already available PCNA studies to understand cross-species incompatibility. They
found that two regions named interdomain connecting loop (IDCL) and J loop structures,
varied significantly among PCNAs.
To validate that these structural differences are indeed accountable for functional
incompatibility, they generated mutants of Neurospora crassa PCNA mimicking IDCL and J
loop structures of PCNA of yeast called Saccharomyces cerevisiae. Genetic analyses
suggested that the mutants were fully functional in Saccharomyces cerevisiae. Further, the
susceptibility of the strains harboring ScPCNA mimics of NcPCNA to various genotoxic agents
was similar to that in yeast cells expressing ScPCNA. It was clear that structures of the IDCL
and J loop of PCNA are critical determinants of interspecies functional compatibility.
Speaking to India Science Wire, the scientists said, “Our study has helped us understand the
details of the complex interplay of binding between PCNA and its partner proteins in cells.
This would help in the development of therapeutic agents that target PCNA. It will be now
possible to ensure that the drugs are highly species specific”.
The study was conducted by researchers from the Laboratory of Genomic Instability and
Diseases and Laboratory of Macromolecular Crystallography at the Department of Infectious
Disease Biology of Institute of Life Sciences, Bhubaneswar.
The team was led by Dr. Narottam Acharya of ILS’s Laboratory of Genomic Instability and
Diseases and Dr. Dileep Vasudevan of ILS’s Laboratory of Macromolecular Crystallography.

The other members were: Premlata Kumari, Rajivgandhi Sundaram, and Kodavati Manohar.
They have published a paper on their work in the Journal of Biological Chemistry.

keywords: disease, molecular mechanism, organism, proliferating cell nuclear antigen,
PCNA, protein, DNA replication, DNA polymerase, structural protein, therapeutic, X-ray
crystal structure, mold, yeast, Institute of Life Sciences, Bhubaneswar, Journal of Biological
Chemistry.

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