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Replication stress has emerged as an early causative event in tumorigenesis, frequently detectable already in precancerous lesions and promoted by activation of well-known oncogenes. These yet-elusive alterations of the replication program activate checkpoint pathways that delay or prevent cell cycle progression in most precancerous lesions, thus representing a crucial barrier against full malignant transformation. At the same time, replication stress creates selective pressure for further mutations that occasionally inactivate checkpoint control, leading to more aggressive cancers. Several tumour suppressors – already well-known as DNA repair factors - were also recently found to play central roles at stalled replication forks, genetically and mechanistically distinct from their function in DNA damage repair. Uncovering how oncogenes and tumour suppressors specifically operate upon endogenous and exogenous replication stress is of key relevance to obtain full mechanistic understanding of cancer onset, especially in individuals carrying known mutations predisposing to cancer.
The goal of this research line is to use our portfolio of imaging and molecular approaches to investigate the role of known oncogenes and tumour suppressors in the replication stress response. We aim to uncover how specific oncogenes exacerbate endogenous sources of genome instability and/or affect the cellular responses to these challenges. Similarly, we attempt to identify novel roles of known tumour suppressors in the replication stress response and to characterize how genetic alterations associated with increased cancer susceptibility impact on genome integrity during replication.
Our work in this area uncovered replication fork remodelling as common and rapid consequence of the activation of multiple oncogenes (e.g. Cyclin E, CDC25A) and identified an important role in fork remodelling and protection of several tumour suppressors, well known in the context of homologous recombination repair (BRCA2, RAD51, RAD51 paralogs, etc.). We now aim to identify endogenous and exogenous sources of genotoxic stress which may potentially engage these factors in limiting fragility of replicating chromosomes, thereby explaining their role in cancer avoidance and chemotherapy response. We also aim to clarify whether, in cell types or tissues particularly exposed to replication stress, even partial inactivation of certain tumour suppressors may lead to increased genomic instability, contributing to the associated cancer susceptibility.
K.J. Neelsen, I.M.Y. Zanini, S. Mijic, R. Herrador, R. Zellweger, A. Ray Chaudhuri, K.D. Creavin, J.J. Blow and M. Lopes (2013). Deregulated origin licensing leads to chromosomal breaks by re-replication of a gapped DNA template. Genes and Development, 27:2537-42.
K. J. Neelsen, I. M. Y. Zanini, R. Herrador and M. Lopes (2013). Oncogenes induce genotoxic stress by mitotic processing of unusual replication intermediates. Journal of Cell Biology, 6: 699-708.
M. Vujanovic, J. Krietsch, M.C. Raso, N. Terraneo, R. Zellweger, J.A. Schmid, A. Taglialatela, J.W. Huang, C.L. Holland, K. Zwicky, R. Herrador, H. Jacobs, D. Cortez, A. Ciccia, L. Penengo and M. Lopes (2017). Replication Fork Slowing and Reversal upon DNA Damage Require PCNA Polyubiquitination and ZRANB3 DNA Translocase Activity. Molecular Cell, 67:882-890.
S. Mijic, R. Zellweger, N. Chappidi, M. Berti, K. Jacobs, K. Mutreja, S. Ursich, A. Ray Chaudhuri, A. Nussenzweig, P. Janscak and M. Lopes (2017). Replication fork reversal triggers fork degradation in BRCA2-defective cells. Nature Communications, 8(1):859.
M. Berti, F. Teloni, S. Mijic, S. Ursich, J. Fuchs, M. D. Palumbieri, J. Krietsch, J. A. Schmid, E. B. Garcin, S. Gon, M. Modesti, M. Altmeyer, and M. Lopes (2020). Sequential role of RAD51 paralog complexes in replication fork remodeling and restart. Nature Communications, 11(1):3531.