BMC Seminar - A Novel Role of the MITF-A Isoform

BMC Seminar Thursday 15 January at 12:30-13:10 in Árnagarður, room 306

Speaker: Thejus B. Venkatesh, PhD student in Cancer Research Laboratory supervised by Stefán Sigurðsson, Faculty of Medicine, University of Iceland.

Title: A Novel Role of the MITF-A Isoform in Maintaining Genomic Stability 

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.

Speaker Bio: Thejus B. Venkatesh is a PhD candidate in the Faculty of Medicine at the University of Iceland, where his doctoral research focuses on isoform-specific functions of the Microphthalmia-associated transcription factor (MITF) in genome stability. Thejus obtained his Master’s degree from the Manipal Institute of Regenerative Medicine, Manipal University, India.  He conducted his thesis research in Prof. Colin Jamora's lab at the Centre for Inflammation and Tissue Homeostasis, InStem (NCBS).