53BP1 and BRCA1: mechanisms driving two antagonistic DNA repair pathways

Dheva Setiaputra, PhD
Postdoctoral fellow
Lunenfeld-Tanenbaum Research Institute
Mount Sinai Hospital in Toronto

This conference is part of the the IRCM Early-Career Scientist Seminar Series (ECS³), a groundbreaking initiative whose mission is to showcase early career scientists. This is a great opportunity to discover the exciting projects of these researchers in training in front of a multidisciplinary audience.

Zoom Link : https://zoom.us/j/98498752788
ID: 984 9875 2788
Code: 476492

About the conference: 
Mutations in the tumor suppressor BRCA1 are prevalent causes of hereditary breast and ovarian cancer. In the first clinical example of a synthetic lethal drug, poly(ADP) ribose polymerase (PARP) inhibitors show exquisite toxicity and specificity for BRCA1-deficient tumors. However, multiple mechanisms for developing PARP inhibitor resistance have been observed. One striking resistance mechanism is through the loss of the DNA repair protein 53BP1. 53BP1 is rapidly recruited to sites of DNA damage and opposes virtually all of BRCA1’s cellular activity. The molecular basis underlying 53BP1 suppression of BRCA1 has been an enduring mystery. Recent discoveries have driven great progress on this front, with the discovery of the downstream effectors of 53BP1. My research delves into the molecular biology of the 53BP1 pathway, defining their recruitment to and biochemical action at sites of DNA breaks. These findings represent a key milestone in the quest to understand the nature of 53BP1-BRCA1 antagonism and its role in PARP inhibitor therapy.

About Dheva Setiaputra:
Dr. Dheva Setiaputra obtained his PhD in Biochemistry and Molecular Biology from the University of British Columbia. In 2017, he joined the team of Dr. Daniel Durocher at the Lunenfeld-Tanebaum Research Institute in Toronto as a postdoctoral researcher. His work aims to characterize a novel DNA repair complex called shieldin and the molecular events allowing its recruitment to DNA double-strand breaks. His contributions to the scientific literature include articles in prestigious journals such as Nature and Molecular Cell, as well as an invited review in EMBO Reports. Dr. Setiaputra’s research is supported by funding from CIHR and by a Cancer Research Society Next Generation Scientist Grant.

Please tell us about your career path, leading up to your application to the ECS³ program:
I completed my undergraduate degree in Biochemistry and Molecular Biology at the University of British Columbia with an Honours Thesis project on the enteropathogenic E. coli type 3 secretion system with Dr. B. Brett Finlay. I then went on to complete my PhD at UBC with Dr. Calvin Yip, focusing on the structural biology of large multiprotein chromatin-modifying complexes purified from Saccharomyces cerevisiae. It was here that I developed my core skills of protein biochemistry and single particle electron microscopy.
Upon completion of my PhD, I sought to expand my research horizon to study disease-relevant topics in a human model system, and to integrate cell biology and genetics into my skillset. To this end, I joined Dr. Daniel Durocher's research group at the Lunenfeld-Tanenbaum Research Institute to study DNA damage repair, particularly in the context of cancer therapy. There I biochemically characterized shieldin, a novel DNA repair complex that facilitates the sensitivity of BRCA1-deficient cells to PARP inhibition. I further explored this pathway by studying the phosphorylation-specific interaction of 53BP1 and RIF1, the two factors directly upstream of shieldin. 
I aim to continue my work in the mechanistic dissection of DNA repair pathways using an integrative approach of biochemical, structural, and genetic techniques. These efforts will inform future endeavors in developing new synthetic lethal therapies rationally designed to target DNA repair-deficient cancers.

Please tell us about your passion for research. What motivates you most about your work?
I am driven by a fascination with nature in all its chaotic complexity. Biochemistry is a particularly elegant manifestation of biology: all life springs from a limited set of genetic and amino acid codes. My focus on DNA repair biochemistry serves two purposes. First, the maintenance of genomic integrity requires a confluence of interacting pathways, providing a rich fountain of fascinating research topics to explore. Second and no less important is the critical role that genome instability holds in cancer. All aspects of cancer touch upon DNA repair, from its development, evolution, and treatment. Cancer is a leading cause of death globally, and my research in mechanisms driving DNA repair has the potential to positively impact these outcomes. I am thus driven by these two aspects of my work: the creative fulfilment it provides and the clinical potential it promises.

Please tell us about the next steps of your career. How will participating in the ECS³ program help you progress as a researcher?
Having just finished my fifth year as a Postdoctoral Researcher with Dr. Daniel Durocher, I am embarking on the next step of my career. Having secured the Cancer Research Society’s Next Generation Scientist Scholarship (which includes a project grant), I am searching for an independent position that will enable me to implement my own research vision. To this end, the ECS³ program is an incredible opportunity to explore one of Canada’s leading research institutions and to network with other Canadian scientists. The professional contacts that it enables will be invaluable for my next career step.

Please tell us about your professional goals. What do you hope to accomplish as a scientist?
My career goal is to lead a world-class research group containing a globally diverse set of talented scientists that explores the cutting edge of DNA repair mechanisms. My research contributions will take the form of high-impact publications that fundamentally changes the field, characterizing novel factors or answering the many outstanding questions on the mechanistic basis of DNA repair pathways. In the long term, I aim to work with the biotech and pharmaceutical industries to translate these findings into interventions or products that benefit society. Finally, I place a special emphasis on creating a nurturing but challenging environment to prepare the next generation of scientists for their chosen career paths.