Doctoral Defence in Biomedical Sciences – Thejus B. Venkatesh

On Wednesday, 4 March, Thejus B. Venkatesh will defend his doctoral dissertation in Biomedical Sciences at the Faculty of Medicine, University of Iceland.

The dissertation is entitled:
A Novel Role of the MITF-A Isoform in Maintaining Genomic Stability.

The opponents are Dr. Lumír Krejčí, Head of Research Group at Masaryk University in Brno, Czech Republic, and Dr. Libor Macůrek, Head of Laboratory at the Institute of Molecular Genetics of the Czech Academy of Sciences in Prague, Czech Republic.

The principal supervisor was Stefán Þ. Sigurðsson, Professor, and the supervisor was Linda Viðarsdóttir, Associate Professor. In addition, the doctoral committee included Eiríkur Steingrímsson, Professor, and Þorkell Guðjónsson, Associate Professor.

Sædís Sævarsdóttir, Professor and Dean of the Faculty of Medicine, will preside over the ceremony, which will take place in the Ceremonial Hall of the University of Iceland (Hátíðasalur) and will begin at 13:00.

Abstract
The genome of all living cells is susceptible to various intra- and extracellular events that can compromise its stability. This genomic stability is crucial for the normal function of all cells, and failure to preserve genome integrity can lead to cancer and other diseases. In the event of DNA damage, cells activate the so-called DNA Damage Response to initiate DNA repair. Replication stress can also cause genomic instability. Replication stress interrupts the DNA replication process by stalling the active replication fork. If there is prolonged replication stress, it leads to genomic instability, which can result in DNA damage, chromosomal abnormalities, and mutations. MITF is a transcription factor best known for its roles in melanocyte biology and melanoma, but its function in genome maintenance remains incompletely understood. While most studies have focused on the MITF-M isoform, the roles of other isoforms remain largely unexplored. Interestingly, many non-melanocytic cells predominantly express the MITF-A isoform. Data presented in this project show that MITF-A is expressed in most tissues, including cancer tissues, and may function as a genome maintenance protein. In this study, we use the osteosarcoma cell line U2OS to uncover the non-melanocyte-specific role of MITF. We found that MITF depletion leads to TP53 accumulation, P21 expression, increased 53BP1 nuclear bodies, and high fork speed, suggesting a protective role in S phase, thus maintaining genomic stability. Differentially expressed genes upon MITF-A isoform knockdown show downregulation of genes associated with DNA replication and DNA repair. Mass spectrometry reveals that MITF-A shows increased interaction with proteins involved in DNA replication and repair, including RPA and PARP1, compared to MITF-M. Notably, data from single-molecule C-trap optical tweezer experiments show that MITF-A, but not MITF-M, stably binds RPA-coated single-stranded DNA. Replication dynamics revealed that MITF-A depletion led to an increase in replication fork speed, which is associated with reduced PARylation. Collectively, this study highlights MITF-A’s role in DNA replication and in maintaining genomic stability.

About the doctoral candidate
Thejus Byranayakanahalli Venkatesh was born in 1995 in Bengaluru, India. He completed his undergraduate studies in Fisheries Science at Karnataka Veterinary, Animal and Fisheries Sciences University in 2017.

Thejus earned a Master’s degree in Stem Cell Technology in 2019 from the Manipal Institute of Regenerative Medicine, Manipal University, India. He conducted his Master’s research in the laboratory of Professor Colin Jamora, where he studied antimicrobial peptides in wound healing and fibrosis at the Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Biology, Bengaluru.

His parents are Venkatesh Murthy and Lakshmi Venkatesh.