[7][8] Should an oncogenic protein, such as those produced by cells infected by high-risk types of human papillomavirus, bind and inactivate pRb, this can lead to cancer.

[11] The working allele need not undergo a mutation per se, as loss of heterozygosity (LOH) is frequently observed in such tumours.

This explains why sufferers of sporadic retinoblastoma are not at increased risk of cancers later in life, as both alleles are functional in all their other cells.

Future cancer incidence in sporadic pRb cases is observed with polynomial kinetics, not exactly quadratic as expected because the first mutation must arise through normal mechanisms, and then can be duplicated by LOH to result in a tumour progenitor.

Generally, phosphorylation causes interdomain locking, which changes pRb's conformation and prevents binding to target proteins.

[8] The pRb-E2F/DP complex also attracts a histone deacetylase (HDAC) protein to the chromatin, reducing transcription of S phase promoting factors, further suppressing DNA synthesis.

Within 72–96 hours of active pRb induction in A2-4 cells, the target DNA replication factor proteins—MCMs, RPA34, DBF4, RFCp37, and RFCp140—all showed decreased levels.

The TFIID binds to the TATA box in order to begin the assembly of the TFIIA, recruiting other transcription factors and components needed in the PIC.

pRb acts as a recruiter that allows for the binding of proteins that alter chromatin structure onto the site E2F-regulated promoters.

Deacetylation, on the other hand, leads to nucleosome formation and thus makes it more difficult for transcription factors to sit on promoters.

pRb recruitment of histone deacetylases leads to the repression of genes at E2F-regulated promoters due to nucleosome formation.

To further add to this point, the HDAC-pRb complex is shown to be disrupted by cyclin D/Cdk4 which levels increase and peak during the late G1 phase.

Cells respond to stress in the form of DNA damage, activated oncogenes, or sub-par growing conditions, and can enter a senescence-like state called "premature senescence".

pRb's role in repressing the transcription of cell cycle progression genes leads to the S phase arrest that prevents replication of damaged DNA.

[25] Throughout early G1, mono-phosphorylated pRb exists as 14 different isoforms (the 15th phosphorylation site is not conserved in primates in which the experiments were performed).

While the exact mechanism is unknown, one hypothesis is that binding to the C-terminus tail opens the pocket subunit, allowing access to all phosphorylation sites.

Additionally, these cells had a markedly decreased growth rate and concentration of DNA replication factors (suggesting G0 arrest).

[31] The classic view of pRb's role as a tumor suppressor and cell cycle regulator developed through research investigating mechanisms of interactions with E2F family member proteins.

Yet, more data generated from biochemical experiments and clinical trials reveal other functions of pRb within the cell unrelated (or indirectly related) to tumor suppression.

pRb is able to be localize to sites of DNA breaks during the repair process and assist in non-homologous end joining and homologous recombination through complexing with E2F1.

pRb has been shown to also be able to recruit protein complexes such as condensin and cohesin to assist in the structural maintenance of chromatin.

Particular forms of pRb have been found to localize to the outer mitochondrial membrane and directly interacts with Bax to promote apoptosis.

[34] This focus has resulted in the recent development and FDA clinical approval of three small molecule CDK4/6 inhibitors (Palbociclib (IBRANCE, Pfizer Inc. 2015), Ribociclib (KISQUALI, Novartis.

However, recent clinical studies finding limited efficacy, high toxicity, and acquired resistance[35][36] of these inhibitors suggests the need to further elucidate mechanisms that influence CDK4/6 activity as well as explore other potential targets downstream in the pRb pathway to reactivate pRb's tumor suppressive functions.

[38] Harvesting the proliferative abilities of cells induced to a controlled "cancer like" state could aid in repairing damaged tissues and delay aging phenotypes.

Embryonic hair cells require pRb, among other important proteins, to exit the cell-cycle and stop dividing, which allows maturation of the auditory system.

In studies where the gene for pRb is deleted in mice cochlea, hair cells continue to proliferate in early adulthood.

Temporarily and precisely turning off pRb in adult mammals with damaged hair cells may lead to propagation and therefore successful regeneration.

pRb can be downregulated by activating the sonic hedgehog pathway, which phosphorylates the proteins and reduces gene transcription.

In addition, Schwann cells, which provide essential support for the survival of neurons, travel with the neurites, extending farther than normal.