New applications of proteins in molecular diagnostics utilizing single-molecule real-time imaging

By Samantha Black, PhD, ScienceBoard editor in chief

July 22, 2019 -- For the first time ever, researchers can view DNA repair using real-time, single-molecule imaging. Scientists from the University of Pittsburgh in collaboration with researchers from Carnegie Mellon and Pitt, induced oxidative stress in telomeres and observed as an enzyme repaired damage. The study was published on July 22, 2019 in Nature Structural and Molecular Biology providing new evidence that cells scout for general DNA damage, and molecular components repair damage as it occurs.

The foundational research conducted the University of Pittsburgh by Bennett Van Houten, Ph.D. and others explored how ultraviolet-damaged DNA-binding protein (UV-DDB) protects against cellular sun damage. UV-DDB is a key protein in human global nucleotide excision repair (NER), a multi-step process which eliminates a wide spectrum of damage causing significant distortions in the DNA structure. This is a particularly important process to repair damage from UV light, which accumulates over time as NER capacity decreases.

Single-molecule real-time imaging revealed that UV-DDB forms transient complexes with enzymes that are essential in base excision repair, facilitating their dissociation from DNA in the process. After this damaged DNA has been removed, DNA polymerase is free to patch the remaining single-stranded portion of DNA. Therefore, researchers suggest that UV-DDB is a critical indicator of DNA damage recognition.

Third-generation sequencing, also known as single molecule sequencing, is different from other methods. It utilizes nanopore based technologies that produce short read lengths by fluorescence detection and sequencing by synthesis. Some of the third generation technologies on the market today include: single molecule real-time (SMRT) sequencing by Pacific Biosciences (PacBio) and nanopore sequencing by Oxford Nanopore Technologies.

The researchers also suggest that this discovery has diagnostic relevance in some rare genetic disorders such as xeroderma pigmentosum (non-functional UV-DDB) where patients are virtually guaranteed to develop skin cancer. Conversely, cancer patients with high levels of UV-DDB often respond better to therapies than those with low UV-DDB levels.

“It’s clear this protein is involved in a very fundamental problem,” Van Houten said. “We could not have evolved out of the slime if we didn’t have good DNA repair.”

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