Final Report Summary - ONIDDAC (Oncogene-Induced DNA Damage in Cancer)
Cancer cells differ from normal cells in that replication of their DNA does not proceed smoothly. Rather, the replication machinery comes off the DNA before replication is completed, requiring the activation of repair pathways to reinitiate and complete DNA replication. However, why cancer cells have problems replicating their DNA (hereafter, referred to as DNA replication stress) and which repair pathways reinitiate DNA replication were unanswered questions. The goal of the ONIDDAC Project was to answer these two questions.
In regard to why cancer cells have DNA replication stress, we found that in normal cells, DNA replication begins from specific sites in the genome (called replication origins), whereas in cancer cells, DNA replication begins also from other sites (new replication origins). These new sites are present inside genes, which creates a conflict between two essential processes in the cell: DNA replication and transcription. These two processes involve the same DNA template and cannot be happening at the same time.
We then showed that the reason that cancer cells have new replication origins is because the signals that stimulate cancer cells to proliferate also shorten the time that cells have to prepare themselves for DNA replication. Thus, DNA replication stress is a necessary byproduct of the drive that cancer cells have to proliferate. These findings were published in Nature (Macheret and Halazonetis, 2018), which is one of the premier journals in the sciences.
The second question relates to which pathway repairs the DNA damage that occurs when DNA replication fails in cancer cells (hereafter, referred to as damaged replication forks; the term fork indicates the structure of partially replicated DNA). We identified the repair pathway and genes that function in this pathway. We showed that this repair pathway, which is called break-induced replication, allows cancer cells to restart DNA replication from the damaged replication forks. We then showed that this pathway is not needed for survival of normal cells. Thus, inhibiting this pathway can result in killing of cancer cells without affecting normal cells. These findings were published in Science (Costantino et al., 2014), which with Nature is one of the premier journals in the sciences, and in more specialized journals (Sotiriou et al., Molecular Cell 2016; Roumelioti et al., EMBO Reports 2016; and others).
In conclusion, the ONIDDAC project has significantly advanced our understanding of cancer and revealed a possible Achilles' heel that we intend to exploit therapeutically.
In regard to why cancer cells have DNA replication stress, we found that in normal cells, DNA replication begins from specific sites in the genome (called replication origins), whereas in cancer cells, DNA replication begins also from other sites (new replication origins). These new sites are present inside genes, which creates a conflict between two essential processes in the cell: DNA replication and transcription. These two processes involve the same DNA template and cannot be happening at the same time.
We then showed that the reason that cancer cells have new replication origins is because the signals that stimulate cancer cells to proliferate also shorten the time that cells have to prepare themselves for DNA replication. Thus, DNA replication stress is a necessary byproduct of the drive that cancer cells have to proliferate. These findings were published in Nature (Macheret and Halazonetis, 2018), which is one of the premier journals in the sciences.
The second question relates to which pathway repairs the DNA damage that occurs when DNA replication fails in cancer cells (hereafter, referred to as damaged replication forks; the term fork indicates the structure of partially replicated DNA). We identified the repair pathway and genes that function in this pathway. We showed that this repair pathway, which is called break-induced replication, allows cancer cells to restart DNA replication from the damaged replication forks. We then showed that this pathway is not needed for survival of normal cells. Thus, inhibiting this pathway can result in killing of cancer cells without affecting normal cells. These findings were published in Science (Costantino et al., 2014), which with Nature is one of the premier journals in the sciences, and in more specialized journals (Sotiriou et al., Molecular Cell 2016; Roumelioti et al., EMBO Reports 2016; and others).
In conclusion, the ONIDDAC project has significantly advanced our understanding of cancer and revealed a possible Achilles' heel that we intend to exploit therapeutically.