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Mol Cell Biol
2015 Dec 28;365:832-45. doi: 10.1128/MCB.00636-15.
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The N Terminus of the Retinoblastoma Protein Inhibits DNA Replication via a Bipartite Mechanism Disrupted in Partially Penetrant Retinoblastomas.
Borysov SI
,
Nepon-Sixt BS
,
Alexandrow MG
.
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The N-terminal domain of the retinoblastoma (Rb) tumor suppressor protein (RbN) harbors in-frame exon deletions in partially penetrant hereditary retinoblastomas and is known to impair cell growth and tumorigenesis. However, how such RbN deletions contribute to Rb tumor- and growth-suppressive functions is unknown. Here we establish that RbN directly inhibits DNA replication initiation and elongation using a bipartite mechanism involving N-terminal exons lost in cancer. Specifically, Rb exon 7 is necessary and sufficient to target and inhibit the replicative CMG helicase, resulting in the accumulation of inactive CMGs on chromatin. An independent N-terminal loop domain, which forms a projection, specifically blocks DNA polymerase α (Pol-α) and Ctf4 recruitment without affecting DNA polymerases ε and δ or the CMG helicase. Individual disruption of exon 7 or the projection in RbN or Rb, as occurs in inherited cancers, partially impairs the ability of Rb/RbN to inhibit DNA replication and block G1-to-S cell cycle transit. However, their combined loss abolishes these functions of Rb. Thus, Rb growth-suppressive functions include its ability to block replicative complexes via bipartite, independent, and additive N-terminal domains. The partial loss of replication, CMG, or Pol-α control provides a potential molecular explanation for how N-terminal Rb loss-of-function deletions contribute to the etiology of partially penetrant retinoblastomas.
Angus,
RB reversibly inhibits DNA replication via two temporally distinct mechanisms.
2004, Pubmed
Angus,
RB reversibly inhibits DNA replication via two temporally distinct mechanisms.
2004,
Pubmed
Arias,
Replication-dependent destruction of Cdt1 limits DNA replication to a single round per cell cycle in Xenopus egg extracts.
2005,
Pubmed
,
Xenbase
Avni,
Active localization of the retinoblastoma protein in chromatin and its response to S phase DNA damage.
2003,
Pubmed
Barrientes,
Glutamic acid mutagenesis of retinoblastoma protein phosphorylation sites has diverse effects on function.
2000,
Pubmed
Bartek,
Mammalian G1- and S-phase checkpoints in response to DNA damage.
2001,
Pubmed
Bell,
DNA replication in eukaryotic cells.
2002,
Pubmed
Blow,
Initiation of DNA replication in nuclei and purified DNA by a cell-free extract of Xenopus eggs.
1986,
Pubmed
,
Xenbase
Bosco,
DNA replication control through interaction of E2F-RB and the origin recognition complex.
2001,
Pubmed
Burke,
Structures of inactive retinoblastoma protein reveal multiple mechanisms for cell cycle control.
2012,
Pubmed
Chew,
pRB phosphorylation mutants reveal role of pRB in regulating S phase completion by a mechanism independent of E2F.
1998,
Pubmed
Chou,
Protein phosphatase 2A regulates binding of Cdc45 to the prereplication complex.
2002,
Pubmed
,
Xenbase
Cosgrove,
Cell cycling and differentiation do not require the retinoblastoma protein during early Xenopus development.
2007,
Pubmed
,
Xenbase
Destrée,
Structure and expression of the Xenopus retinoblastoma gene.
1992,
Pubmed
,
Xenbase
Dryja,
Molecular etiology of low-penetrance retinoblastoma in two pedigrees.
1993,
Pubmed
Edwards,
MCM2-7 complexes bind chromatin in a distributed pattern surrounding the origin recognition complex in Xenopus egg extracts.
2002,
Pubmed
,
Xenbase
Fung,
The Rb gene suppresses the growth of normal cells.
1993,
Pubmed
Gambus,
A key role for Ctf4 in coupling the MCM2-7 helicase to DNA polymerase alpha within the eukaryotic replisome.
2009,
Pubmed
Goodrich,
How the other half lives, the amino-terminal domain of the retinoblastoma tumor suppressor protein.
2003,
Pubmed
Goodrich,
The retinoblastoma tumor-suppressor gene, the exception that proves the rule.
2006,
Pubmed
Hassler,
Crystal structure of the retinoblastoma protein N domain provides insight into tumor suppression, ligand interaction, and holoprotein architecture.
2007,
Pubmed
Henson,
The retinoblastoma gene is involved in malignant progression of astrocytomas.
1994,
Pubmed
Jakubowska,
Novel RB1 gene constitutional mutations found in Polish patients with familial and/or bilateral retinoblastoma.
2001,
Pubmed
Kang,
Interaction between human Ctf4 and the Cdc45/Mcm2-7/GINS (CMG) replicative helicase.
2013,
Pubmed
Knudsen,
Inhibition of DNA synthesis by RB: effects on G1/S transition and S-phase progression.
1998,
Pubmed
Knudsen,
RB-dependent S-phase response to DNA damage.
2000,
Pubmed
Kubota,
Retinoblastoma gene mutations in primary human prostate cancer.
1995,
Pubmed
Lan,
DNA damage invokes mismatch repair-dependent cyclin D1 attenuation and retinoblastoma signaling pathways to inhibit CDK2.
2002,
Pubmed
Lee,
Claspin, a Chk1-regulatory protein, monitors DNA replication on chromatin independently of RPA, ATR, and Rad17.
2003,
Pubmed
,
Xenbase
Lefévre,
A T to C mutation in the polypyrimidine tract of the exon 9 splicing site of the RB1 gene responsible for low penetrance hereditary retinoblastoma.
2002,
Pubmed
Madine,
Xenopus replication assays.
1997,
Pubmed
,
Xenbase
Mukherjee,
Cell cycle arrest by transforming growth factor beta1 near G1/S is mediated by acute abrogation of prereplication complex activation involving an Rb-MCM interaction.
2010,
Pubmed
Newport,
A major developmental transition in early Xenopus embryos: I. characterization and timing of cellular changes at the midblastula stage.
1982,
Pubmed
,
Xenbase
Niculescu,
Effects of p21(Cip1/Waf1) at both the G1/S and the G2/M cell cycle transitions: pRb is a critical determinant in blocking DNA replication and in preventing endoreduplication.
1998,
Pubmed
Numata,
Interaction of human MCM2-7 proteins with TIM, TIPIN and Rb.
2010,
Pubmed
,
Xenbase
Otterson,
Incomplete penetrance of familial retinoblastoma linked to germ-line mutations that result in partial loss of RB function.
1997,
Pubmed
Pacek,
A requirement for MCM7 and Cdc45 in chromosome unwinding during eukaryotic DNA replication.
2004,
Pubmed
,
Xenbase
Qin,
Identification of a growth suppression domain within the retinoblastoma gene product.
1992,
Pubmed
Riley,
Mutations of N-terminal regions render the retinoblastoma protein insufficient for functions in development and tumor suppression.
1997,
Pubmed
Royzman,
ORC localization in Drosophila follicle cells and the effects of mutations in dE2F and dDP.
1999,
Pubmed
Sellers,
Stable binding to E2F is not required for the retinoblastoma protein to activate transcription, promote differentiation, and suppress tumor cell growth.
1998,
Pubmed
Simon,
A Ctf4 trimer couples the CMG helicase to DNA polymerase α in the eukaryotic replisome.
2014,
Pubmed
Smythe,
Systems for the study of nuclear assembly, DNA replication, and nuclear breakdown in Xenopus laevis egg extracts.
1991,
Pubmed
,
Xenbase
Sterner,
Negative regulation of DNA replication by the retinoblastoma protein is mediated by its association with MCM7.
1998,
Pubmed
,
Xenbase
Sánchez,
A constitutional homozygous mutation in the RB1 gene in a patient with unilateral retinoblastoma.
2000,
Pubmed
Waga,
The DNA replication fork in eukaryotic cells.
1998,
Pubmed
Walter,
Regulated chromosomal DNA replication in the absence of a nucleus.
1998,
Pubmed
,
Xenbase
Walter,
Regulation of replicon size in Xenopus egg extracts.
1997,
Pubmed
,
Xenbase
Walter,
Initiation of eukaryotic DNA replication: origin unwinding and sequential chromatin association of Cdc45, RPA, and DNA polymerase alpha.
2000,
Pubmed
,
Xenbase
Walter,
Evidence for sequential action of cdc7 and cdk2 protein kinases during initiation of DNA replication in Xenopus egg extracts.
2000,
Pubmed
,
Xenbase
Wong,
Cdc45 limits replicon usage from a low density of preRCs in mammalian cells.
2011,
Pubmed
Xu,
Enhanced tumor cell growth suppression by an N-terminal truncated retinoblastoma protein.
1994,
Pubmed
Yan,
TopBP1 and DNA polymerase-alpha directly recruit the 9-1-1 complex to stalled DNA replication forks.
2009,
Pubmed
,
Xenbase
Yan,
TopBP1 and DNA polymerase alpha-mediated recruitment of the 9-1-1 complex to stalled replication forks: implications for a replication restart-based mechanism for ATR checkpoint activation.
2009,
Pubmed
Yang,
Tumor suppression by a severely truncated species of retinoblastoma protein.
2002,
Pubmed
Zhu,
Mcm10 and And-1/CTF4 recruit DNA polymerase alpha to chromatin for initiation of DNA replication.
2007,
Pubmed
,
Xenbase
