DNA Repair Protein to Have a Novel Role in Cancer Disease, Scientists Unveil
Researchers in Tufts University have found that a certain cellular protein which has a key role in repairing damaged DNA molecules could also help the cancer development.
Mitch McVey, Assistant Professor of Biology, and his team of researchers report that PolQ (DNA polymerase theta) could promote a wrong repair process, supposed to be the cause of mutations, cell death and even cancer. The research has been published in the open-access PLoS Genetics journal, the 1st of July edition.
Scientists have been aware for many years that the DNA polymerase theta is in a way related to cancer development, but the exact cellular role it has is difficult to reveal, according to McVey. It is known that its action during incorrect DNA repair might have implications for those biologists who analyze genomic modifications associated with cancer.
The DNA molecule is double stranded and shaped in the form of a spiral staircase. The two strands are connected together by nucleotides like adenine, cytosine, guanine and thymine, which naturally complement each other. Under normal circumstances, a guanine nucleotide corresponds to a cytosine, while an adenine corresponds to a thymine.
During a cell’s life, it may occur that the staircase is cut off into two molecules. The breaks are to be repaired if cells are supposed to replicate accurately and transmit their genetic material. An important part of these breaks is fixed fast and accurately during a process named HR (homologous recombination). This process uses for repair a template formed of an intact DNA copy. There is, however, a second process, named end-joining repair, which is susceptible of errors. It stitches back together the broken stranded ends without considering the original sequence. Thus, the ends of the strands may be modified by addition or removal of little DNA segments that could alter the genomic architecture.
Mitch McVey and Amy Marie Yu, a doctoral student, have demonstrated an alternative structure of end-joining after studying how repair goes on when DNA ligase 4 is absent. DNA ligase 4 is an important protein which connects together two broken ends of DNA.
Two things have been observed during the analysis of breaks inaccurately repaired in Drosophila melanogaster, the fruit fly. One thing was that extra nucleotides were added to the DNA strands were the breaks were present. Secondly, the insertions were tightly related to the DNA original sequences that were adjacent to the breaks.
The authors have shown that polymerase theta has a dominant role to play in the alternative repair process. It reads first the genetic material present in the DNA neighboring the break and constructs a copy of its structure. The copy of the DNA is then used as a molecular sliver which holds together the ends of the broken strand until they are able to join permanently. The PolQ protein is also believed to be able to unwind the sequences of DNA in the neighborghood of a break and this way facilitates alternative end-joining.
Levels of the protein have been demonstrated to be higher in many types of tumors present at the human, as other groups of researchers have previously shown. McVey’s team is currently working to find out if an alternative type of end-joining depending on the PolQ protein is eventually involved in human cancer. If this is found to be true, then there would be a new target for developing new cancer drugs and this would be the PolQ protein. The first goal of the team is to establish which parts of the protein are playing an active role in alternative end-joining. This could give the team a road map for studying how the activity of the protein has to be altered in order to achieve the expected results.
The National Science Foundation together with the Ellison Medical Foundation has funded the work of McVey’s team.
