Loss of proofreading not enough to cause cancers
A DNA polymerase losing some proofreading activity causes distinctive mutations, yet cancers only happen when other systems are damaged too.
New cells are made when an existing cell divides in two. Each time a cell divides, it duplicates its DNA so that each new cell inherits a complete copy. Molecular machines called DNA polymerases make these DNA copies. The main DNA polymerases, known as delta and epsilon, can “proofread” the new DNA, which ensures that the genetic information stored in the DNA is correctly copied. Cells also use another system, called mismatch repair, to catch any errors that get missed by the polymerases.
Cancer cells contain many mutations in genes that regulate the growth and production of new cells, which is why cancers grow out of control and produce tumors. Research shows that many cancer cells with high numbers of mutations have lost their proofreading ability. Yet it is not clear if the loss of proofreading is enough to cause cancers, or if other systems, such as mismatch repair, must also be defective.
Hodel, de Borja, Henninger et al. examined human cells grown in the laboratory to understand the importance of proofreading in cancer. It turns out that even the partial loss of polymerase epsilon proofreading could lead to distinctive mutations. Yet, these mutations were repaired by mismatch repair, so they actually are only found in cells when mismatch repair is also defective. This result demonstrates that the lack of proofreading is not enough to cause a large number of mutations. These cancers only happen when other systems are damaged too.
These new findings add to the current understanding of the origins of mutations in cancers and how mutations accumulate over time. It should lead scientists to further investigate the patterns of mutations that happen in the absence of proofreading. It may also enhance our knowledge of proofreading-deficient cancers.
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