Líffræðifélag Íslands - biologia.is
Líffræðiráðstefnan 2023
Höfundar / Authors: Drífa H. Guðmundsdóttir, Linda Viðarsdóttir, Þorkell Guðjónsson og Stefán Sigurðsson
Starfsvettvangur / Affiliations: Háskóli Íslands
Kynnir / Presenter: Drífa Hrund Guðmundsdóttir
Replication stress is a major source of genome instability and a common feature of most cancer types. Unresolved replication stress can cause DNA double strand breaks (DSBs) and other chromosome aberrations, which can dramatically impact normal cell physiology. In such cases, the tumor suppressor P53 plays a central role in preserving genome integrity by promoting cell cycle arrest and apoptosis. Microphthalmia associated transcription factor (MITF) is crucial for melanocyte development and survival, and a major melanoma oncogene, amplified in 10-20% of melanomas. Studies on the role of MITF in other tissues are, however, scarce. Here we demonstrate that MITF has an important role in maintaining genome stability beyond the melanocyte lineage. MITF knockdown in the osteosarcoma cell line U2OS show strong signs of replication stress and chromosomal abnormalities, which results in P53 mediated G1 arrest and apoptosis. Moreover, we show that MITF depletion activates P53 via Large tumor suppressor kinase 2 (LATS2) a key kinase in the Hippo pathway. Our findings indicate that the genome maintenance function of MITF is not limited to the melanocyte linage, as MITF knockdown caused genome instability across different cell types. Collectively, this study highlights the role of MITF as a genome maintenance factor and uncovers a potential connection between MITF and the Hippo pathway, which is frequently dysregulated in cancer.