Israeli scientists at the Weizmann Institute of Science have discovered that it takes two different types of enzymes to carry out an essential form of DNA repair -- one that can make the difference between life and death.
A recent study conducted by Prof. Tzvi Livneh of the Weizmann Institute’s Biological Chemistry Department, graduate students Sigal Shachar and Omer Ziv, and researchers from the US and Germany, revealed how the error-prone repair works. The findings of the study were published recently in the EMBO Journal.
Livneh, however, has been working on the problem for the past 20 years.
DNA Repair: How it Works
The team found that the repair system proceeds in two steps and requires two types of enzymes, belonging to the family of enzymes called DNA polymerases, which synthesize DNA.
First, one repair enzyme, “the inserter,” does its best to fit in a genetic “letter” into the gap, opposite the damaged site in the DNA molecule; several enzymes can perform this initial step, which often results in the insertion of an incorrect genetic letter.
Next, another enzyme, “the extender,” helps to restore regular copying of DNA by attaching additional DNA letters after the damaged site; only one repair enzyme is capable of performing this vital second step.
'Life Could Not Exist'
“Considering that the DNA of each cell is damaged about 20,000 times a day by radiation, pollutants and harmful chemicals produced within the body, it’s obvious that without effective DNA repair, life as we know it could not exist," Livneh said.
"Most types of damage result in individual mutations – genetic ‘spelling mistakes’ – that are corrected by precise, error-free repair enzymes," he continued. "Sometimes, however, the damage results in more than a mere spelling mistake."
That kind of damage can cause gaps in the DNA which prevent the DNA molecule from being copied when the cell divides -- much like an ink blot or a hole on a book page interferes with reading, he explained.
"So dangerous are these gaps that the cell resorts to a sloppy but efficient repair technique to avoid them -- it fills in the missing DNA in an inaccurate fashion.
"Such repair can save the cell from dying, but it comes at a price: this error-prone mechanism is a major source of mutations,” he noted.
The "stopgap" process was discovered about 10 years ago by scientists at the Weizmann Institute, and elsewhere around the world.
New Knowledge Could Lead to Cancer Cure
Understanding how this major form of DNA repair works can have significant clinical implications, Livneh added.
Since defects in DNA repair increase the risk of cancer, clarifying the mechanism might one day make it possible to enhance the process in people whose natural DNA repair is deficient.
In addition, manipulating this mechanism can improve the effectiveness of cancer drugs, he pointed out, since cancer cells can resist chemotherapy by exploiting their natural repair mechanisms. Blocking these mechanisms may help overcome this resistance, leading to a targeted destruction of the cancerous tumor, he said.
Prof. Livneh’s research is supported by the Helen and Martin Kimmel Institute for Stem Cell Research; the estate of Lore F. Leder; and Esther Smidof, Geneva, Switzerland. He is the incumbent of the Maxwell Ellis Professorial Chair in Biomedical Research.