The DNA damage response from exogenous double-strand breaks is well-studied, but the response to stalled replication forks that results in strand cleavage is less well understood. Homologous recombination (HR) has been predominantly studied as a mechanism of DNA double-strand break repair, but the major role of HR proteins in protecting the genome may be due to the homology-dependent repair of cleaved DNA replication forks. The recruitment of HR proteins to blocked or cleaved replication forks depends on BRCA1-BRCA2 pathway of HR, which we know is defective in a significant number of human cancers. The role of both proteins may not be the same in managing replication forks compared to double-strand breaks with two ends. By studying the consequences of a blocked DNA replication fork in detail, the goal is to develop new potential strategies for the therapy of BRCA-pathway deficient cancers.
The first aim will determine events that occur as a result of replication fork block (RFB) and how the RFB is cleaved resulting in replication fork collapse.
The second aim will determine what happens when there are defects in HR, resulting in genomic instability. Since HR-deficiency is a tumor-specific phenotype, the understanding of replication-associated events provides opportunities for novel therapeutics. For example, we need to understand how fatal chromosomal aberrations are created by replication-associated breaks in HR-deficient cells. The role of Replication Protein A, RAD52, and alternative end-joining are all potentially important in determining cell fate. The knowledge from these proposed experiments should allow new insight for treating human cancers with defects in this pathway.
Genomic instability of a significant number of human cancers is created by defects in homologous recombination, which is generated by spontaneous events connected to DNA replication. This application proposes to understand the events that occur when a replication fork is blocked and when the fork is broken. Since DNA replication related errors are the major source of genomic instability in this type of cancer, understanding their mechanism should allow a new approach to targeting the cancer-specific defect. The results should provide a basis for improved biological targeting of homologous recombination deficiency for cancer therapy.
|Setton, Jeremy S; Powell, Simon N (2018) A new role for a tumor-suppressing protein. Elife 7:|
|Russell, James; Pillarsetty, Nagavarakishore; Kramer, Robin M et al. (2017) In Vitro and In Vivo Comparison of Gemcitabine and the Gemcitabine Analog 1-(2'-deoxy-2'-fluoroarabinofuranosyl) Cytosine (FAC) in Human Orthotopic and Genetically Modified Mouse Pancreatic Cancer Models. Mol Imaging Biol 19:885-892|
|Jelinic, Petar; Eccles, Laura A; Tseng, Jill et al. (2017) The EMSY threonine 207 phospho-site is required for EMSYdriven suppression of DNA damage repair. Oncotarget 8:13792-13804|
|O'Rourke, Kevin P; Loizou, Evangelia; Livshits, Geulah et al. (2017) Transplantation of engineered organoids enables rapid generation of metastatic mouse models of colorectal cancer. Nat Biotechnol 35:577-582|
|Lok, Benjamin H; Gardner, Eric E; Schneeberger, Valentina E et al. (2017) PARP Inhibitor Activity Correlates with SLFN11 Expression and Demonstrates Synergy with Temozolomide in Small Cell Lung Cancer. Clin Cancer Res 23:523-535|
|Powell, Simon N (2016) BRCA1 loses the ring but lords over resistance. J Clin Invest 126:2802-4|