RB in DNA Repair: Paul H. Huang, Rebecca Cook and Sibylle Mittnacht

Oncotarget, Vol. 6, No.
25
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Editorial
RB in DNA repair
Paul H. Huang, Rebecca Cook and Sibylle Mittnacht
The retinoblastoma protein (RB1) has a welldocumented role as a key regulator of cell cycle
progression by controlling the G1/S phase transition
[1]. RB1 has also emerged as a multi-functional protein
involved in a wide range of biological processes including
transcriptional regulation by recruiting chromatin
remodelling enzymes, DNA replication via interaction
with DNA polymerase complex components and apoptosis
through association with the mitochondria [1]. In our
recently published study [2], we add to this functional
repertoire by demonstrating that RB1 and its paralogs
p107 and p130 play a central role in DNA double strand
break (DSB) repair by non-homologous end joining
(NHEJ).
By employing an affinity purification proteomics
strategy, our study finds that RB1, through its amino
terminal (RB1N) domain, binds to components of the
NHEJ machinery including Ku70, Ku80 and DNAdependent protein kinase (DNA-PK). We further show
using structure-guided mutations that these interactions are
dependent on a conserved cyclin wedge homology surface
within RB1N. Importantly, engineered RB1 mutants
disabled for Ku70 binding were unable to rescue NHEJdependent DNA repair when expressed in RB1-negative
cells. Consistent with these data, cells with RB1 loss
displayed increased frequency of chromosomal aberrations
upon irradiation which is a hallmark of defective NHEJ.
A key finding of our study is that the capacity of RB1 to
regulate NHEJ is genetically separate from its canonical
functions in cell cycle progression or E2F transcriptional
regulation.
Our study adds to an increasing body of evidence
that RB1 is important for maintaining genomic stability
in response to overt DNA damage. RB1 depletion
leads to an increase in chromosome instability (CIN),
manifesting in aneuploidy or polyploidy [3]. Widespread
chromosome gains and loss associated with RB1 loss is
attributed to centromere dysfunction and the failure to
recruit components of the Condensin II complex, leading
to a defect in chromosome condensation during mitosis
[3]. RB1 also regulates global chromatin structure and
consequently gene expression through the recruitment of
key chromatin modifying enzymes. These include histone
deacetylases HDAC 1 and 2, histone methyltransferase
SUV4 and SWI/SNF chromatin remodelling complex
catalytic subunit Brahman/SWI2-related gene (BRG1),
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all of which have been shown to be important for DNA

DSB repair [1, 4]. Furthermore, RB1 binds to tumour
protein p53 binding protein 1 (53BP1) via a methylated
K810 residue which directly links RB1 function to the
DNA damage response [5]. Together these data argue
that RB1 is a key player in preventing genome instability
through a complex interplay of regulatory events including
centromere function, chromatin structure and direct
recruitment by DNA damage repair proteins.
Other than the well-established context in cancer
and the role of RB1 as a bona fide tumour suppressor,
RB1 may also be important in DNA damage surveillance
during aging. Human cells are naturally subjected to
DNA damage insults, such as oxidative stress from
metabolic processes, which if left unrepaired would
lead to accumulation of damage within both the nuclear
and mitochondrial DNA. Amitotic cells such as skeletal
muscle cells or neurons are particularly susceptible to
accumulation of DNA damage over time and it is thought
that this is likely to be a prominent cause of aging.
Consistent with this idea, mice with defective mutations
in the NHEJ proteins Ku70 and Ku80 display a premature
aging phenotype without increased cancer incidence levels
[6]. Gene deletion in mice has provided indirect evidence
that RB1 is necessary for maintaining survival of fully
differentiated post-mitotic neurons in mice [7]. Acute loss
of RB1 in neurons induces the expression of cell cycle
proteins with a corresponding increase in DNA double
strand breaks, leading to cell death in vivo. A tempting
hypothesis is that RB1 is part of the NHEJ surveillance
machinery in the face of naturally occurring DNA damage
in amitotic cells and may be a key player for preventing
age-associated neurodegenerative disorders.
There remain many open questions as to the role
of RB1 in facilitating NHEJ. These include establishing
if RB1 is itself recruited to sites of DNA DSBs, the
mechanism(s) by which RB1 assembles DNA repair
proteins and accessory factors at DSBs, and if there
is a direct link between RB1 function in NHEJ and its
ability to regulate chromatin structure through modifiers
such as HDAC 1 and 2. Future work in elucidating these
mechanisms will enable the exploitation of this novel
function of RB1 for new therapies in cancer and ageassociated disorders
20746
Oncotarget
Paul Huang: The Institute of Cancer Research, Division of

Cancer Biology, Chester Beatty Laboratories and Cancer
Cell Signalling, UCL Cancer Institute, University College
London, London, UK
Correspondence to: Paul Huang, email paul.huang@icr.
ac.uk
Keywords: retinoblastoma protein, DNA repair
Received: July 28, 2015
Published: August 22, 2015
References
1.
Dick FA, et al. Nat Rev Mol Cell Biol. 2013; 14: 297-306.
2.
Cook R, et al. Cell Rep. 2015; 10: 2006-18.
3.
Manning AL, et al. Nat Rev Cancer. 2012; 12: 220-6.
4.
Dunaief JL, et al. Cell. 1994; 79: 119-30.
5. Carr SM, et al. Proc Natl Acad Sci. U S A. 2014; 111:

11341-6.
6.
Li H, et al. Mol Cell Biol. 2007; 27: 8205-14.
7.
Andrusiak MG, et al. J Neurosci. 2012; 32: 14809-14.
www.impactjournals.com/oncotarget
20747
Oncotarget

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Oncotarget, Vol. 6, No.

all of which have been shown to be important for DNA

Paul Huang: The Institute of Cancer Research, Division of

Cook R, et al. Cell Rep. 2015; 10: 2006-18.

Manning AL, et al. Nat Rev Cancer. 2012; 12: 220-6.

Dunaief JL, et al. Cell. 1994; 79: 119-30.

5. Carr SM, et al. Proc Natl Acad Sci. U S A. 2014; 111:

Li H, et al. Mol Cell Biol. 2007; 27: 8205-14.

Andrusiak MG, et al. J Neurosci. 2012; 32: 14809-14.

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