The cell cycle overturned: Mechanisms by which viruses interfere with key components of the cell cycle progression

Abstract

The cell cycle is regulated by a complex network of signaling pathways and molecular machineries aimed at the faithful division of the complete genome into two identical daughter cells. Errors in this regulation can lead to aberrant chromosome segregation and often cause a form of chromosomal instability (CIN). This cellular phenotype is frequently found in cancer and other malignancies and can arise through mutations in important regulatory tumor suppressor genes or the overactivation of oncogenes. Besides cellular oncogenes, numerous viral oncogenes have been described over the last decades. The targets of these viral proteins are often important regulators of mitosis. This viral influence on mitotic regulation can interfere with normal chromosome segregation, increasing the risk of CIN. This review discusses how viral proteins interfere with the cellular machinery that ensures faithful chromosome segregation, using a selection of examples. Viruses can deregulate cell cycle progression by interacting with proteins involved in cell cycle checkpoints or DNA repair, activating or inhibiting the anaphase promoting complex (APC/C), causing centrosome overduplication, (de)stabilizing microtubules, or disturbing cytokinesis. Examples are provided for each of these interactions, intermittently focusing on retroviruses and especially the Human Immunodeficiency Virus 1 (HIV-1). Implications are drawn for cancer research and virology, and a possibility for the use of CINinducing viral proteins as a mechanism to enhance oncolytic viral therapy is considered. The interplay between viruses and the cell cycle is an important field that requires more interdisciplinary efforts in research and can contribute greatly to our knowledge of the origins of cancer and possible treatments.