Practice question

Retinoblastoma tumor suppressor Rb forms central brake of G1 progression. Hypophosphorylated form present in quiescent G0 and early G1 binds E2F transcription factor family E2F1-3 together with DP1/2 dimer partners and recruits chromatin repressors histone deacetylase HDAC1/2, Suv39h1 H3K9 methyltransferase, BRG1/BRM SWI/SNF subunits and DNMT1 to promoters, maintaining hypoacetylated closed chromatin silencing S-phase genes. Cyclin D-CDK4/6 complexes activated by mitogens phosphorylate Rb at C-terminal residues such as Ser780 Ser795 partially weakening binding to LXCXE motif proteins and permitting initial transcription of Cyclin E. Cyclin E-CDK2 then adds phosphorylations at additional pocket sites including Ser612 causing conformational shift that promotes dissociation through Pin1 prolyl isomerase action. Hyperphosphorylated Rb fully releases E2F, allowing transcription of genes required for nucleotide synthesis, replication licensing and S phase progression, thus permitting entry into S phase. Phosphorylation persists through S G2 M phases until PP1 phosphatase dephosphorylates Rb in late mitosis restoring repressive complex for next G1. Loss of Rb pathway via mutation or viral oncoprotein E1A binding results in constitutive E2F activity driving unchecked proliferation hallmark of many cancers.