Weill Cornell Medicine
We envisage that the new checkpoint control mechanisms of genome regulation that we have discovered present a one-of-a-kind niche for targeted cancer intervention. Exploiting our unique chemical biology toolsets and cross-disciplinary expertise, we will hijack these novel interactions and pathways to ultimately treat disease.
Yimon Aye was born and raised in Burma. She moved to the UK to study for sixth form (high school) and then read chemistry at Oxford University, UK (2004). She moved to Harvard University, USA, achieving a Ph.D. in organic chemistry under the supervision of Professor Dave Evans (2009). She then moved to Massachusetts Institute of Technology to research the cellular and biochemical regulatory mechanisms of the enzyme ribonucleotide reductase (RNR) with Professor JoAnne Stubbe. In her independent career at Cornell University that began in mid-2012, she set out to understand a non-canonical signaling paradigm known as redox signaling and novel moonlighting functions of proteins involved in DNA biogenesis. This impetus culminated in the development of T-REX that illuminates target-specific redox signaling trajectories with high spatiotemporal control. Her parallel investigations into DNA metabolic enzymes have led to the discovery of new check points involved in genome maintenance and tumor suppression of therapeutic significance.
The Aye Lab deploys a unique blend of chemical methodology, biotechnology, and mechanistic oncology and exploits cultured cells, worm, and fish as experimental models. Her independent early contributions to science have been recognized by: Beckman Young Investigator (2014); NSF CAREER (2014); NIH Director’s New Innovator (2014); Sloan Fellowship (2016); American Chemical Society CRT Young Investigator (2016); American Chemical Society WCC Rising Star Chemist (2016); International Chemical Biology Society Rising Star Chemical Biologist (2016); and Office of Naval Research Young Investigator (2017) Awards.
Targeting novel moonlighting functions of RNR-a in B-cell lymphomas
Exquisite ‘checks and balances’ must be in place to maintain metazoan genome stability. Endowed with the unique and essential function of converting ribonucleotides to deoxyribonucleotides (the fundamental building blocks for DNA), the enzyme ribonucleotide reductase (RNR) has arguably been the central player in genome surveillance since the beginning of DNA-based life. The fundamental importance of this biochemical function and the complexity of RNR biochemistry have meant many other aspects of RNR function and regulation have been largely overlooked.
“The project builds on a game-changing idea that is based on some interesting data we have developed over the past 4 years. Altogether these results give us confidence that we have uncovered an important niche that may provide novel cancer interventions. This award promises accelerated success toward achieving that goal. Furthermore, the Pershing award mechanism will uniquely give us a boost to move our early data from model systems to investigate translational implications. This is the time when not only the funding, but the ‘pastoral’ side of Pershing will be a real bonus to us.”
In a search for new functions of this ancient enzyme, we undertook a large-scale search for novel interacting proteins and discovered two novel binding partners of a specific subunit of RNR (RNR-α). Our initial data reveal that by controlling RNR-α’s compartmentalization and resulting interactions with these two binders, RNR-α can either promote or suppress DNA synthesis. Importantly, these two novel coregulators carry hotspot mutations in diffuse large B-cell lymphomas (DLBCL), the most common type of non-Hodgkin lymphoma in the US where ~40% of patients do not benefit from current standard regimens. Our data further show that these RNR-α-dependent new cellular signaling axes are dynamically responsive to nucleotidepool imbalance and unfolded protein response—markers deregulated in DLBCL. Intriguingly, these newlyidentified signaling pathways also respond to a specific class of anti-lymphoma drugs in clinical use. The mechanistic advances we establish herein will unveil previously-unappreciated anti-proliferative ‘checkpointcontrol mechanisms’ of fundamental importance in genome surveillance. Understanding these novel antilymphoma-drug-relevant pathways/targets promises a profound impact on our current knowledge of cancerdrug-resistance mechanisms and successful therapeutic innovations.
“Innovations make even the experts stand up and say ‘WOW! Why did I not think of that?’ Perhaps that is why innovations are often made by people from without the specific field who lack preconceptions.”