The applicant, Katharina Schlacher, is committed to a lifelong academic career and aims to become an independent investigator and enabling mentor at the frontier of cancer research in the field of replication fork protection. Katharina proposes three-year plan that will optimally equip her to becoming a successful independent research investigator in this challenging funding environment. The proposed project seeks to study cellular and molecular processes of replication fork protection by tumor-suppressor.
The specific aims of the project are as follows:
Aim1 Investigating replication fork instability in tumor cells, Aim2 Testing FA-mediated replisome stability, and Aim3 Determining RAD51 paralog tumor suppressor functions during fork protection. The proposed Aims will obtain critical knowledge on the impact of this new area of research to tumor biology, to understand its role in tumor cells and to initiate detailed insights into fork protection. This project will strengthen her abilities nd this new research area that is at the heart of her independent career, during which she aspires to decipher the mechanism of replication fork protection, identify new players of this pathway and open doors to understanding its implications with regards to stem cell biology and therapeutic strategies Under the mentorship of Dr. Maria Jasin (MSKCC) and co-mentor Dr. Hong Wu (UCLA), the candidate will meet regularly with her mentors, interact with other pertinent experts in the field, and supplement her training with structured meetings, conferences, and coursework. The award will produce sufficient preliminary data for independent funding applications, and enable her to acquire key technical knowledge, experience, and data needed to build and substantiate this new research area, to successfully jump-start her independent career and to secure an independent faculty position in health-related research. She will gain key extra and complementary experience in IPOND, Rad51 paralogs, and Talen technology for genomic engineering as well as on replication fork instability in mammary, ovarian and pancreatic tumor cells. Dr. Schlacher and her mentors thus view this project as a critical enabling opportunity for her to meet the challenges of her research goals and aspirations.
This project investigates mechanistic and cellular aspects of a new DNA replication protection pathway, which involves Fanconi Anemia and breast cancer suppressors. Replication fork protection has critical implications to current chemotherapeutic strategies and likely also constitutes a tumor suppressor mechanism. The proposed project will obtain key-knowledge about this new pathway with respect to therapy and its mode of action, and so contribute to NIH goals to improve public health. The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the Critique section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The Resume and Summary of Discussion section above summarizes the final opinions of the committee.
|Roy, Sunetra; Luzwick, Jessica W; Schlacher, Katharina (2018) SIRF: Quantitative in situ analysis of protein interactions at DNA replication forks. J Cell Biol 217:1521-1536|
|Roy, Sunetra; Tomaszowski, Karl-Heinz; Luzwick, Jessica W et al. (2018) p53 orchestrates DNA replication restart homeostasis by suppressing mutagenic RAD52 and POL? pathways. Elife 7:|
|Liu, Wenpeng; Zhou, Mian; Li, Zhengke et al. (2016) A Selective Small Molecule DNA2 Inhibitor for Sensitization of Human Cancer Cells to Chemotherapy. EBioMedicine 6:73-86|
|Guo, Cai; Kumagai, Akiko; Schlacher, Katharina et al. (2015) Interaction of Chk1 with Treslin negatively regulates the initiation of chromosomal DNA replication. Mol Cell 57:492-505|