Abstract
Faithful transmission of genetic information is only possible with the structural and functional integrity of the genome. PTEN has been recognized as a guardian of the genome since the identification of its noncanonical localization and function in the nucleus. Yet, the role of PTEN in guarding the genome relies on integration of diverse mechanisms elicited by its canonical activity in antagonizing PI3K as well as emerging noncanonical functions. In the nucleus, PTEN maintains the structural integrity of chromosomes and the architecture of heterochromatin by physically interacting with chromosomal and nucleosomal components. PTEN also controls the functional integrity of key genetic transmission machineries by promoting proper assembly of the replisome and mitotic spindles. Deregulation of PTEN signaling impairs genome integrity, leading to spontaneous replication/mitotic stress and subsequent stress tolerance. Identification of novel targets of PTEN signaling and illumination of the interplay of diverse PTEN pathways in genome maintenance will help us better understand mechanisms underlying tumor evolution and therapeutic resistance.