Forty-year-old theory promoted to fact

Twenty thousand hits per day – that’s the average dose of damage sustained by the genes within each cell of our body. How are innumerable mutations avoided? In a study published in the October issue of Molecular Cell, Weizmann Institute researchers have proved the existence of a vital repair mechanism used by cells to correct this damage and showed that it’s responsible for about 85% of what are termed “last-resort” repairs.
 

Genes can be damaged by a variety of factors, such as ultraviolet light, cigarette smoke, or certain types of viruses. Such damage, if left unrepaired, can cause mutations, which can lead to disease. The “first resort” for genetic repair is most often a mechanism that works on an “all or nothing” basis: when unable to precisely correct the damage, it stops in its tracks, leading to what can be an even more harmful effect – the death of the cell.

 

Fortunately, nature has provided cells with two alternative, last-resort repair systems that can take command when the first rescue mechanism fails. One system is inaccurate – it repairs genes while permitting the formation of a relatively small number of mutations. Though this poses a certain risk, it ensures the cell’s continued existence. Equally important, it increases genetic diversity, allowing natural selection, the driving force of evolution, to come into play.
 

The other last-resort repair system was hypothesized by scientists in the 1960s yet was never proved until the current study. This system, which relies on the help of “sister chromosomes,” enables the cell to repair genetic damage without the risk of creating mutations. (During the process of cell division, each chromosome - the structure in the nucleus that contains DNA - gives rise to two identical “sister” chromosomes. These move on to the two separate cells created from the dividing cell.)

According to this theory, if one of the sister chromosomes is damaged, the other can serve as a back-up system of sorts. The damaged genetic information can be restored precisely using the corresponding DNA segment from the other, identical chromosome. That segment detaches itself from the intact “sister” chromosome and moves over to the defective chromosome, helping to repair the damage. The gap created in the donor chromosome is refilled by using the segment from its remaining intact DNA strand (DNA consists of two matching strands) as a template. Both chromosomes end up with a complete, undamaged genetic segment.
 

In the new study, Prof. Zvi Livneh, head of the Biological Chemistry Department at the Weizmann Institute of Science, has for the first time observed this repair mechanism in action. Furthermore, Livneh and his team, which consisted of graduate students Ala Berdichevsky and Lior Izhar, also showed that the repair mechanism based on a genetic “donation” from the sister chromosome is unusually common: it is responsible for 85% of last-resort repairs – those performed by alternative repair systems when the major, “all-or-nothing” repair mechanism fails. The second last-resort system – the relatively inaccurate repair mechanism that allows the creation of mutations – is responsible only for some 15% of repairs.
 

The repair mechanisms, studied in E. coli bacteria, are well preserved throughout evolution, which means that variants of these mechanisms exist and operate in more developed organisms, including humans. The new findings could thus provide important clues into human disease and help advance gene therapy. In addition, these findings could help tackle bacteria’s mounting resilience to antibiotic drugs, which is credited to their ability to quickly mutate into resistant forms.
 

Donor Support: Dolfi and Lola Ebner Center for Biomedical Research, the Levine Institute of Applied Science and the M.D. Moross Institute for Cancer Research.
Prof. Livneh is the incumbent of the Maxwell Ellis Professorial Chair in Biomedical Research.