Table 1.

pRB Loss Undermines Genome Stability: an Overview

Described effect on Aneuploidy, CIN and/or DNA Damage response	Type of Lesion/model	Date	Ref(s)
Cell cycle analysis of Rb deficient fibroblasts shows they have an increased incidence of aneuploidy	Primary fibroblasts isolated from Rb mutant mouse embryos	1996	[91]
Rb loss or inactivation allows for re-replication following drug induced mitotic arrest	Rb−/− mouse embryonic fibroblasts (MEFs); E7 expressing fibroblasts, p16−/− and p21−/− MEFs	1997/1998	[92] [93]
Loss of Rb, but not p107 or p130 impairs G1/S checkpoint response to damaging inducing agents	Rb−/− MEFs	1998	[94]
Loss of the Rb family prevents appropriate G1 arrest in response to DNA damage	Rb−/−; p107−/−; p130−/− Triple Knockout (TKO) MEFs	2000	[95, 96]
pRB interacts with Hec1 and hsRB expression in a yeast temperature sensitive hec1 allele suppresses segregation errors	Heterologous yeast system expressing human pRB and human Hec1	2000	[55]
Deficiency of Rb causes increased loss of a marker gene	Rb−/− mouse embryonic stem (ES) cells with an inserted chromosomal marker	2002	[97]
Rb null cells exhibit increased levels of aneuploidy	Rb−/− MEFs	2002	[98]
pRB depletion leads to upreguation of the mitotic spindle assembly checkpoint protein Mad2 and near diploid aneuploidy	Rb−/− MEFs, mouse and human cell lines expressing pRB-targeting short hairpins or E1A expression constructs	2004	[44]
Loss of Rb leads to increased ploidy and failure of the DNA damage checkpoint response	Conditional Rb knockout in Mouse Adult Fibroblasts (MAFs)	2004	[99]
Cells lacking Rb function exhibit increased double strand breaks and compromised cell cycle arrest following genotoxic stress.	Conditional Rb knockout in (MAFs)	2004/2005	[76, 80]
Rb loss leads to increased ploidy following serum starvation	Rb−/− and Rb−/−p107−/− MEFs	2005	[100]
Rb loss leads to increased levels of aneuploidy and tetraploidy, independent of p53 status	Rb1−/−, p107−/−; p130−/−, and TKO MEFs	2005	[62]
Loss of pRB leads to E2F1-mediated accumulation of DNA double strand breaks	Acute depletion of pRB in human fibroblast and osteosarcoma cell lines	2005/2006	[101, 102]
Acute loss of Rb induces centrosome amplification and aneuploidy	Conditional Rb deficient MEFs	2006	[45]
Disruption of Rb LXCXE pocket reduces pericentromeric H4K20me3 and induces ploidy changes	Rb1ΔL/ΔL, Rb1−/− mouse ES cells	2006	[46]
Acute and sustained liver specific Rb loss promotes ploidy changes	Liver-specific conditional Rb knockout mice	2005/2007	[48, 103]
Rb loss leads to deregulation of DNA synthesis and elevated ploidy	Conditional Rb knockout in MAFs	2007	[49]
pRB inactivation compromises the G2/M DNA damage checkpoint	Stable pRB depletion in U2OS cells	2007	[104]
Whole chromosome gains and losses are coincident with progression from retinoma to retinoblastoma	Genetic RB1 mutation/human tumor samples	2008	[40]
Rbf1 loss leads to defects in condensin II chromatin association and chromatin condensation, and abnormal chromosome segregation	Drosophila Rbf1 mutants	2008	[60]
Acute depletion of pRB leads to supernumerary centrosomes, formation of micronuclei and aneuploidy. Depletion of CENPA partially suppresses the number of aneuploid cells.	Acute siRNA pRB depletion in human fibroblasts and HCT116 tumor cells	2009	[42, 105]
Suggests a functional link between pRB and the kinetochore protein Hec1 influences chromosome segregation	Transient and stable depletion of pRB in HCT116 tumor cells	2010	[53]
pRB loss causes defects in chromosome cohesion and condensation, centromere dysfunction, and promotes high rates of chromosome missegregation	Acute and stable depletion of pRB in human epithelial cells; Drosophila Rbf1 mutants	2010	[106]
An Rb1 mutant that retains it’s ability to regulate E2F exhibits defects in chromatin condensation, promotes more aggressive tumors, and accelerates loss of heterozygosity in a tumor model	Rb1ΔL/ΔL; TRP53+/− and Rb1ΔL/ΔL; TRP53−/− knock in mouse tumor models and MEFs and mouse ES cells	2010	[107]
Loss of the Rb family of proteins compromises the G2 DNA damage checkpoint, allowing cells to enter mitosis with unrepaired damage, thereby promoting genome instability and aneuploidy	TKO MEFs	2010	[78]
Replication induced DNA damage due to pRB pathway defects is caused by nucleotide deficiency and leads to genome instability	Primary keratinocytes infected with E6/E7 expression vector; Cyclin E overexpression in BJ fibroblasts	2011	[79]