2023-10-17 00:30:08
Double-strand breaks in DNA (double strand-breaks – DSB), if not repaired correctly, threaten the integrity of the genome and promote the development of cancer cells. DNA DSBs can be caused by many external factors. During the cell cycle, they appear just as much during interphase as during mitosis. While DSBs formed in interphase are commonly repaired by mechanisms such as homologous recombination (HR) or non-homologous end joining (NHEJ), the repair of DSBs formed during mitosis were previously considered unrepaired during the latter. Indeed, the classic repair mechanisms are inactive during this cellular process since the DNA is then too condensed.
Polθ: a new player in repair during mitosis
A joint research team (Institut Curie/Inserm/CEA) led by Dr Raphael Ceccaldi, has updated the role and functioning of Polθ. This polymerase enzyme is indeed capable of inducing repairs of breaks during mitosis. The researchers also showed that it is a kinase, PLK1 (polo-like-kinase 1), specifically present during mitosis, which activates Polθ.
Polθ, Achilles heel of cancer cells
The discovery takes on particular significance in the context of cancer. Indeed, mutations in the BRCA1 and BRCA2 genes, responsible for at least half of breast cancers, are involved in DSB repair. These mutations render cells deficient in homologous recombination (HR).
Cancer cells are then cells whose minimum genomic stability to survive depends mainly on the activity of Polθ. Loss of Polθ in these cells would result in defective repair of mitotic DSBs, thereby greatly increasing genomic instability and leading to targeted cancer cell death.
New potential therapeutic targets
The discovery therefore opens the way to new therapeutic targets. By targeting Polθ or its regulators, such as PLK1, it would become possible to disrupt the repair of mitotic DSBs in cancer cells, potentially leading to their selective death.
Cancer treatments, such as chemotherapy and radiation therapy, can damage healthy cells in addition to cancer cells, causing unwanted side effects. By specifically targeting the repair of mitotic DSBs, it would be possible to reduce these side effects by maximizing the impact on tumor cells.
Reference :
Polθ is phosphorylated by PLK1 to repair double-strand breaks in mitosis.
Camille Gelot, Marton Tibor Kovacs, Simona Miron, Emilie Mylne, Alexis Haan, Liza Boeffard-Dosierre, Rania Ghouil, Tatiana Popova, Florent Dingli, Damarys Loew, Josée Guirouilh-Barbat, Elaine Del Nery, Sophie Zinn-Justin & Raphael Ceccaldi.
Nature – September 6, 2023
1697506773
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