Thursday, November 10, 2022 at 12:00 PM
This grand round has already taken place.
November 10th, 2022 1.00 AMA PRA Category 1 Credit Hours
Description
Genomic instability is a hallmark of cancer cells and a potential source of tumorigenesis. A major cause of genomic instability is replication fork stalling at sites of DNA damage or abnormal DNA structure. I am using Escherichia coli Tus/Ter replication fork barrier (RFB) to induce site-specific replication fork stalling on a mammalian chromosome. Tandem duplications (TDs) in primary cells lacking BRCA1 are induced specifically by a Tus/Ter block but not by a conventional double strand break (DSB), indicating specificity for the stalled fork response. Intriguingly, breast and ovarian cancers lacking BRCA1 similarly acquire large numbers of small (~10 kb) TDs, which we have termed “Group 1” TD. Thus, the Tus/Ter system recapitulates the BRCA1-specific regulation of Group 1 TD formation observed in human breast and ovarian cancer.
I found that the stalled fork motor protein—FANCM acts synergistically with BRCA1 to suppress Tus/Ter-induced TDs. I discovered a novel synthetic lethal interaction between Brca1 and Fancm loss in mouse embryonic stem (ES) cells and in breast and ovarian cancer cells. These findings suggest that FANCM may be a promising therapeutic target in BRCA1-linked breast and ovarian cancer. I am exploring the novel FANCM-BRCA1 synthetic lethal interaction in cancer cells to determine the mechanism of synthetic lethality. Further, I am delineating the chromatin environment and protein dynamics at the stalled fork and studying how alterations in these processes contribute to the FANCM-BRCA1 synthetic lethal interaction. This holistic approach will provide a full picture of the mechanism of FANCM-BRCA1 synthetic lethal interactions and will encourage me, in the future, to develop high throughput screens for specific small molecule inhibitors targeting the key players involved in this pathway, as novel therapeutics in BRCA1-linked breast and ovarian cancer.
Dates and Times
Start: 11/10/2022 12:00 PM
End: 11/10/2022 1:00 PM
Objectives
(1) Audience will learn how genome instability relates to the cancer development
(2) Audience will learn various repair outcomes (error-free and error-prone) from replication fork stalling and how it is different from DNA-Double strand break
(3) Audience will learn concept of synthetic lethality and how it can be applied to target drug sensitive and resistant cancer cell
Speakers
Accreditation
The School of Medicine, State University of New York at Stony Brook, is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
The School of Medicine, State University of New York at Stony Brook designates this live activity for a maximum of 1.00 AMA PRA Category 1 Credits ™. Physicians should only claim the credit commensurate with the extent of their participation in the activity.
Need help with this Grand Round Session?
Please contact the Grand Round coordinator listed below:
Jessica Mattera
Department: Pathology Department
Phone: (631) 444-2169
Email: jessica.mattera2@stonybrookmedicine.edu