The RB protein: more than a sentry of cell cycle entry

Genomic instability is a hallmark of cancer. It fuels cancer progression and therapy resistance. As 'the guardian of the genome', the tumor suppressor protein p53 protects against genomic damage. Canonically, the retinoblastoma protein (RB) is 'the sentry of cell cycle entry', as it dictates whether a cell enters the cell cycle to divide. However, the RB pathway also controls myriad non-canonical cellular processes, including metabolism, stemness, angiogenesis, apoptosis, and immune surveillance. We discuss how frequent RB pathway inactivation and underlying mechanisms in cancers affect these processes. We focus on RB's - rather than p53's - 'guardian of the genome' functions in DNA replication, DNA repair, centrosome duplication, chromosome segregation, and chromatin organization. Finally, we review therapeutic strategies, challenges, and opportunities for targeting RB pathway alterations in cancer.