Safeguarding the genome is essential for cells’ proper functions, and more importantly for safe and efficacious applications involving pluripotent stem cells and adult stem cells. However, how pluripotent or somatic stem cells maintain genome integrity during self-renewal, differentiation, and reprogramming is still largely unknown. In the past year, we continue to characterize a novel small molecule that was previously identified and shown to protect and enhance repairing of stem cell genome under genotoxic stress conditions. We found that the small molecule can accelerate DNA damage repair in several human cell types. Furthermore, we have designed and synthesized its new analogs and identified its structure-activity-relationship. Moreover, we attempted affinity pull-down for target identification and began to test several target candidates. A better understanding of mechanisms involved in regulating genome stability and DNA repair in stem cells, and more importantly developing new and practically useful approaches (e.g., small molecules) to improve genome maintenance and damage repair would be highly desirable.
Reporting Period:
Year 2
Safeguarding the genome is essential for cells’ proper functions, and more importantly for safe and efficacious applications involving pluripotent stem cells and adult stem cells. However, how pluripotent or somatic stem cells maintain genome integrity during self-renewal, differentiation, and reprogramming is still largely unknown. In the past year, we continue to characterize a novel small molecule that was previously identified and shown to protect and enhance repairing of stem cell genome under genotoxic stress conditions. We found that the small molecule can accelerate DNA damage repair in several human cell types. Furthermore, we have designed and synthesized its new analogs and identified its structure-activity-relationship. Moreover, we attempted affinity pull-down for target identification and began to test several target candidates. A better understanding of mechanisms involved in regulating genome stability and DNA repair in stem cells, and more importantly developing new and practically useful approaches (e.g., small molecules) to improve genome maintenance and damage repair would be highly desirable.
Reporting Period:
Year 3
During the reporting period, we have made significant progress toward the following research aims: (1). We further mechanistically characterized how PTM regulates H2A.X (key mediator of DNA repair), and DNA sequence specificity (genome-wide fragile sites). (2). Through SILAC-based chemical proteomics, the interacting proteins of PTM were identified and mechanistically characterized. (3) In human stem cells, PTM mediated homologous recombination to protect cells and enhance genome editing was further characterized.
Grant Application Details
Application Title:
A novel druggable mechanism to safeguard stem cell genome
Public Abstract:
Safeguarding the genome is essential for cells’ proper functions, and more importantly for safe and efficacious applications involving pluripotent stem cells and adult stem cells. However, how pluripotent or somatic stem cells maintain genome integrity during self-renewal, differentiation, and reprogramming is still largely unknown. We recently identified a small molecule drug that exhibits unprecedented abilities in maintaining and enhancing genome stability of pluripotent stem cells under stress conditions. The proposed studies aim to uncover the small molecule’s mechanisms and utilities in human pluripotent and adult stem cells. These studies will lead to improved understanding to safeguard stem cell genome, provide a safer and more robust approach in stem cell ex vivo expansion, and allow new therapeutic development toward treating diseases and aging associated with genome instability as well as promoting in vivo stem cell protection.
Statement of Benefit to California:
The proposed studies will lead to improved understanding to safeguard stem cell genome, provide a safer and more robust approach in stem cell ex vivo expansion, and allow new therapeutic development toward treating diseases and aging associated with genome instability as well as promoting in vivo stem cell protection.
