Eris Duro, a PhD student in John Rouse’s team in the MRC Protein Phosphorylation Unit, has discovered a complex of two proteins in human cells, termed MMS22L and TONSL, that plays a vital role in repairing DNA breaks that arise during the process of DNA replication.
During each cell cycle, the genome is duplicated so that there is enough DNA for two daughter cells when cells divide. A major problem is that the protein machineries responsible for replicating DNA frequently encounter obstacles that block their progression. In addition, the DNA replication machineries often encounters nicks in the DNA backbone, and this causes chromosomes to break and “replication forks” to collapse. This, in turn, can give rise to chromosome translocations, aneuploidy or cell death. In this sense, it is vital that broken replication forks are detected rapidly and repaired efficiently and accurately.
MMS22L and TONSL bind rapidly to broken DNA replication forks, where they initiate a process known as “homologous recombination”, an ancient mechanism for repairing broken DNA replication forks. In particular, MMS22L and TONSL are required for the loading of the RAD51 recombinase onto DNA ends and this initiates homologous recombination. RAD51 loading was also known to require the tumour suppressor BRCA2 that is frequently mutated in breast and ovarian cancers. Furthermore, the consequences of depleting MMS22L and TONSL from cells are remarkably similar to those caused by BRCA2 mutations. This raises the possibility that mutations in MMS22L or TONSL could cause cancers.
Eris’ discovery of the MMS22L–TONSL complex is published in the “Articles in Press” section of the current issue of Molecular Cell.