Molecular and functional characterization of the topoisome in lymphocyte activation

Purpose: To characterize the mechanism of the MYC-induced “topoisome” complex and assess its contribution in MYC function under physiological and pathological conditions.Background: MYC is a potent transcription factor and major driver for tumorigenesis. However, targeting MYC has proven to be challenging due to its inability to bind drugs.

In their recent work, Dr. Baranello (KI/SWE) and Dr.

Levens (NIH/USA) discovered that MYC nucleates with topoisomerase 1 and 2 (TOP1 and TOP2, or TOPs) into the topoisome and stimulates the activity of TOP1 and TOP2 to promote the removal of detrimental DNA supercoiling generated during transcription and replication.

The topoisome is likely to be responsible for MYC-induced fast cellular growth.Project organisation: By using structural and genomic approaches I will: 1) define the architecture of the topoisome and the molecular details of the complex (at the NIH); 2) develop a novel sequencing approach to map topoisomes engaged on DNA (at the NIH); 3) study the function of the topoisome in lymphocyte activation and in MYC-dependent lymphoma (at KI).

Performing the experiments in presence of drugs and peptides targeting TOPs –and topoisomes– will reveal potential novel vulnerabilities that can be therapeutically exploited in anticancer therapy.Relevance: The work might provide the rationale for a unique approach to target MYC and TOPs in cancer.

If successful, a MYC-targeting therapy has the potential for tailored treatment of many tumors.