Emerging roles of RIF1 in mitosis

Abstract

Faithful chromosome segregation during cell division requires precise coordination of kinase– and phosphatase–driven signaling pathways. Defects in this balance can cause chromosome missegregation and cytokinesis failure, resulting in genomic instability. Rap1-interacting factor 1 (RIF1) is known for its interphase functions in DNA damage repair, DNA replication timing, and chromatin organization. However, recent work has established RIF1 as a critical mitotic regulator that functions primarily through its role as a protein phosphatase 1 (PP1) adaptor. During early mitosis, the localization of RIF1 to the mitotic apparatus is thought to be actively suppressed by mitotic kinases, including cyclin-dependent kinase 1 (CDK1), aurora kinase B (AURKB), and polo-like kinase 1 (PLK1), preventing premature PP1 engagement and dephosphorylation. Following anaphase onset, relief of this inhibition allows PLK1-interacting checkpoint helicase (PICH)–dependent recruitment of RIF1 to ultrafine anaphase DNA bridges (UFBs), where RIF1-associated PP1 activity determines pathway choice for UFB resolution. In cytokinesis, PLK1 promotes RIF1 recruitment to the midbody, where PP1 antagonizes AURKB activity to enable timely cytokinetic abscission. Herein, we review recent advances defining the spatial and temporal regulation of RIF1 during mitosis, highlight unresolved mechanistic questions in UFB resolution and PP1 regulation, and discuss emerging links between the mitotic functions of RIF1 and genomic instability.