RB1 - dismech genes

Normal function · from ai-gene-review (P06400, commit 79fe13b38970) · AI-generated, not KB evidence

RB1 encodes the retinoblastoma-associated protein (pRb / p105-Rb / p110-RB1), the founding member of the pocket protein family and a nuclear, chromatin-bound tumor suppressor. Its core evolved activity is to enforce the G1 restriction point by binding activator E2F transcription factors (E2F1/2/3) through the RB_A/RB_B pocket domains, masking their transactivation domains and recruiting chromatin-modifying corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases, polycomb factors) to E2F-target promoters required for S-phase entry. Activity is switched off by sequential cyclin-CDK phosphorylation: Cyclin D-CDK4/6 and Cyclin E-CDK2 progressively phosphorylate ~16 Ser/Thr sites, with an early reversible intermediate phosphorylation at T373/S608 followed by cooperative C-terminal hyperphosphorylation (S780, S807/S811, T826) that fully releases E2F. Genome-wide ChIP studies show RB1 occupies thousands of loci across promoters, enhancers, and CTCF-bound sites, and the same scaffolding activity supports several non-canonical functions that are well documented but mechanistically downstream of the E2F-repression core: repression of RNA polymerase III transcription (via TFIIIB binding), genome maintenance (interactions with Ku70/Ku80/XRCC5/XRCC6 in cNHEJ and with BRG1 in HR-coupled programs), heterochromatin/SAHF formation in cellular senescence, and lineage-specific transcriptional cooperation with non-E2F partners (RUNX2, AR, CEBPD, PU.1). RB1 is the mutated locus in hereditary retinoblastoma and is recurrently lost in many adult tumors; its functional state is a clinically actionable biomarker for CDK4/6 inhibitor response.

RB1 functions as the canonical transcriptional corepressor of the pocket protein family. Through its RB_A/RB_B pocket domains it binds activator E2F transcription factors (E2F1/2/3) on the promoters of S-phase genes, masks their transactivation domains and recruits chromatin-modifying corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, polycomb and DNA methyltransferase activities) to durably silence the E2F transcriptional program in G0/G1 cells. This activity defines the G1 restriction point and is the most highly conserved evolved function of pocket proteins. RB1 is held in this active corepressor state when hypo- or mono-phosphorylated, and is sequentially inactivated by Cyclin-CDK complexes (Cyclin D-CDK4/6, Cyclin E-CDK2) that hyperphosphorylate ~16 Ser/Thr sites (e.g. T373, S608, S780, S807/S811, T826), releasing E2F to drive S-phase entry.

molecular function: transcription corepressor activity · directly involved in: negative regulation of G1/S transition of mitotic cell cycle; negative regulation of DNA-templated transcription · locations: nucleus; chromatin · in complex: Rb-E2F complex

In the knowledge base · computed from kb/ at build time

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

Disorder	Relationship	Where the gene appears
Kidney Sarcoma	somatic driver	scoped to subtype: Renal LMS
Large Cell Neuroendocrine Carcinoma	somatic driver somatic	mechanism: RB1 Biallelic Inactivation
Liposarcoma	cooperating somatic	scoped to subtype: PLPS
Thymic Neuroendocrine Carcinoma	somatic driver somatic	mechanism: RB-Axis Tumor Suppressor Loss
Bladder Urothelial Carcinoma	untyped Somatic Inactivation
Gallbladder Cancer	untyped Somatic Loss-of-Function Mutation
Merkel Cell Carcinoma	untyped Somatic Mutations (in MCPyV-negative MCC)
Osteosarcoma	untyped Somatic mutation / germline predisposition
Pineoblastoma	untyped Germline and Somatic Alterations	mechanism: RB1 Pathway Inactivation subtype: PB-RB1
Prostate Adenocarcinoma	untyped Somatic loss of function
Retinoblastoma	untyped Germline and Somatic Mutations germlinesomatic loss of function	mechanism: Germline RB1 First-Hit Inactivation; Somatic RB1 Second-Hit Inactivation
Small Cell Lung Cancer	untyped Somatic Inactivating Mutation
Transitional Cell Carcinoma	untyped somatic
Urinary Bladder Small Cell Neuroendocrine Carcinoma	untyped Somatic Mutations	mechanism: Recurrent TP53 and RB1 Tumor-Suppressor Alterations
Vulvar Carcinoma	no genetic record	mechanism: HPV E7-Mediated pRB Binding

ClinGen gene–disease validity · snapshot 2026-10-03 · matched to entries by MONDO

An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.

ClinGen disease	MOI	Classification	dismech entry
retinoblastoma MONDO:0008380	AD	Definitive 2020-07-30	Retinoblastoma untyped

Mechanism modules · computed from kb/

evading_growth_suppressors via Thymic Neuroendocrine Carcinoma, Urinary Bladder Small Cell Neuroendocrine Carcinoma
germline_two_hit_tumor_predisposition via Retinoblastoma
viral_oncogenesis via Vulvar Carcinoma