Team 2 (J.S. Hoffmann): to understand how replication stress generates genomic instability
Our understanding of human cancer and our ability to treat and prevent it depend critically on our knowledge of the mechanisms and pathways of tumor evolution. It has become apparent that genetic instability, a hallmark of cancer cells, plays a major role in the cancer process. The past decade has seen a dramatic advance in our understanding of how genomic integrity is compromised in cancer and has revealed that replicative stress (RS) in S phase, which leads to endogenous double-strand breaks (DSB) and under-replicated genomic loci, is a highly relevant mechanism, placing RS studies at the forefront of cancer research. The nature of RS essentially stands for the accumulation of recombinogenic stretches of single-stranded DNA (ssDNA), which can form at processed DSB which derive from stalled replication forks. It has been established that RS induces directly chromosomal instability and the current model proposes that at least some DSBs generated at collapsed forks during replication stress are repaired in an error prone manner by end joining repair events leading to gross chromosomal rearrangement such as chromosomal translocations. In addition to these well-documented direct consequences of replication problems, the fate of under-replicated genomic loci which can enter into mitosis, be converted to complex broken DNA structures and then transmitted to G1 daughter cells, is totally undervalued. Yet, since the accurate transmission of genetic information to the next cell generation is one of the main process that guarantee the maintenance of genomic stability within a cellular clone, it is obvious that the stability of the genome might be affected by the transmission of unresolved DNA regions to the next cell generation. Therefore, the nature of the molecular mechanisms responsible for the transmission process and its impact on the next cell generation need to be deeply decoded.
The team, by exploring these issues, have ultimately opened novel research lines. We have discovered that daughter cells can modify their own replication program to better ensure replication of DNA sequences that experienced problems in the previous cell cycle. This process may explain why a cancer cellular clone could sustain efficient DNA replication and cell proliferation despite a high degree of endogenous replicative stress and unstable genome, a major question that is still unsolved. Our research lines have also revealed a novel crosstalk pathway between replication and repair of damaged DNA, a process that could equip a malignant cellular clone with an escape mechanism in presence of chemotherapeutic treatments which target DNA replication forks and exacerbate replicative stress and, hence, provoke therapeutic resistance.
Our main objectives:
- Study one mechanism used by mother cells to limit the transmission of the replication problems: replication of problematic chromosomal domains and late DNA synthesis by different DNA polymerases in late G2 or early mitosis.
- Monitor the fate of the transmitted damages in G1 daughter cells (if and how they are repaired) and the potential role of the repair DNA polymerase theta in the process.
- Analyze a totally unexplored field, the impact of transmitted DNA damage on one of the most robust biological process that takes place in G1: the establishment of the DNA Replication initiation program.
- Explore the physiological and pathological relevance of the process of DNA damage transmission and its impact on DNA replication of daughter cells.
- Evaluate how these processes contribute to the therapeutic response of tumors treated with the multiple anticancer agents that impede the progression of the replication forks.
Jean-Sébastien Hoffmann's team is supported by La Ligue Contre le Cancer, INCa, ANR, Fondation Toulouse Cancer Santé and Région Occitanie; furthermore, the team is part of Labex TOUCAN