DNA damage response and cancer therapeutics through the lens of the Fanconi Anemia DNA repair pathway
Bhattacharjee and Nandi Cell Communication and Signaling
DNA damage response and cancer therapeutics through the lens of the Fanconi Anemia DNA repair pathway
Fanconi Anemia (FA) is a rare, inherited genomic instability disorder, caused by mutations in genes involved in the repair of interstrand DNA crosslinks (ICLs). The FA signaling network contains a unique nuclear protein complex that mediates the monoubiquitylation of the FANCD2 and FANCI heterodimer, and coordinates activities of the downstream DNA repair pathway including nucleotide excision repair, translesion synthesis, and homologous recombination. FA proteins act at different steps of ICL repair in sensing, recognition and processing of DNA lesions. The multi-protein network is tightly regulated by complex mechanisms, such as ubiquitination, phosphorylation, and degradation signals that are critical for the maintenance of genome integrity and suppressing tumorigenesis. Here, we discuss recent advances in our understanding of how the FA proteins participate in ICL repair and regulation of the FA signaling network that assures the safeguard of the genome. We further discuss the potential application of designing small molecule inhibitors that inhibit the FA pathway and are synthetic lethal with DNA repair enzymes that can be used for cancer therapeutics.
DNA repair; Fanconi Anemia (FA) signaling network; DNA damage response; Cancer therapeutics; Synthetic lethality; Combination Therapy Genomic instability; Interstrand crosslink (ICL); Homologous recombination; Translesion synthesis
Fanconi Anemia (FA), a rare genetic cancer-susceptibility
syndrome is a recessive autosomal or X-linked genetic
]. FA is characterized by genomic instability,
bone marrow failure leading to progressive aplastic
anemia, chromosomal fragility and heightened
susceptibility to cancer, particularly acute myelogenous leukemia
]. With an incidence of ~1–5 per 1,000,000
births, many FA patients suffer from developmental
disorders and physical abnormalities ranging from short
stature, abnormal skin pigmentation, organ malformation,
hypogonadism, and developmental delay . Patients are
often diagnosed with early onset of solid tumors including
squamous cell carcinomas of the head and neck, cervical
cancer and liver tumors [
]. FA was first described by
the Swiss pediatrician Guido Fanconi in 1927 while
treating a family of five siblings, three of whom presented with
developmental birth defects and died from an early-onset
of clinical features resembling pernicious anemia .
Additional clinical features included microcephaly, vitiligo
and hypoplasia of the testes [
]. After nearly four decades
another article reported an accumulation of large number
of chromatid breaks in the blood lymphocytes of FA
]. Due to high frequencies of chromosomal
abnormalities, predominantly chromatid breaks during S-phase
of the cell cycle, researchers concluded that FA patients
have impaired double strand break repair (DSBR) [
Also despite the varied clinical phenotypes of the disease,
a defining characteristic of FA cells is the cellular
hypersensitivity to DNA crosslinking agents such as mitomycin
C (MMC), chemotherapeutic agent cisplatin (CDDP), and
diepoxybutane (DEB) [
]. These crosslinks block
ongoing DNA replication, DNA transcription, and if left
unrepaired, activate cell apoptosis . The observation
that a functional FA pathway is required for processing
damage after exposure to crosslinking agents has led to
a great deal of research implicating the FA pathway in
crosslink repair and the maintenance of genomic
]. Additionally, since the FA pathway has also
been associated with cancer susceptibility, a better
understanding of the mechanisms and roles of this
pathway will enable the development of better-targeted
In this review will we will focus on the repair of DNA
interstrand crosslinks (ICLs) by the FA network of
proteins. We aim to summarize our current understanding
of ICL repair largely based on studies in the mammalian
system. We will discuss the etiology of ICLs, the DNA
repair pathways involved in the repair of ICLs, FA
proteins, FA-DNA repair network and conclude with a
perspective on targeting the FA pathway to identify
anticancer therapeutic strategies.
ICLs are highly toxic DNA lesions that prevent the
separation of the Watson and Crick strands of the double helix
by covalently linking the two DNA strands. In doing so
ICLs block critical cellular processes such as transcription
and replication. ICLs can lead to gross-chromosomal
aberrations like chromosome deletion, chromosome loss
and DNA breaks [
]. The ability of ICLs to impede DNA
replication and thereby block cell proliferation is used in
chemotherapy to treat various cancers [
Chemotherapeutic drugs like cisplatin and its derivatives, carboplatin
and oxaliplatin are bifunctional alkylating agents that form
]. Although ICL repair remains poorly
understood, factors involved in nucleotide excision repair
(NER), homologous recombination (HR), and translesion
synthesis (TLS) have been implicated in ICL removal and
subsequent repair [
]. In non-proliferating cells such as
quiescent cells, NER plays an important role in ICL
recognition and removal [
]. In contrast, in cells
undergoing genome duplication, the DNA replication machinery
serves as a sensor for ICLs. This subsequently triggers
DNA damage checkpoint activation and initiates repair. In
these S-phase cells, HR and TLS are the DSBR pathways
employed for ICL repair . In the past several years the
role of FA network of proteins in the detection and repair
of ICLs by promoting HR has been much better
Mechanistic insights into replication-dependent ICL repair
ICL repair is initiated when a traveling replication fork is
stalled due to collision with a lesion on the DNA that
triggers the activation of the DNA repair machinery [
]. Structure-specific endonucleases generate incisions on
either side of the ICL, followed by TLS and then
HRmediated replication fork restart allows for the rescue of
such stalled forks [
] (Fig. 1). It is important to note that
majority of ICL repair in dividing cells is coupled to DNA
replication. In mammalian cells, irrespective of the
cellcycle phase where the ICL is formed, the repair occurs
exclusively during S-phase i.e., replication-dependent ICL
Mechanistic details of replication-dependent ICL
repair emerged from studies in Xenopus egg extracts
where replication-coupled ICL repair was reconstituted
in vitro by using site-specific ICL templates [
a plasmid containing a site-specific ICL is incubated in
this cell-free system, replication initiates at multiple
origins of replication sites on the plasmid with two
replication forks converging on the ICL. Initially, the leading
strand polymerases stall ~20 nucleotides from the
crosslink due to steric hindrance by the replisome (replicative
helicase complex consisting of Cdc45, MCM2-7 and the
GINS, collectively referred to as the CMG complex, and
the replication polymerase) [
] which travels along
the leading strand template and pauses at the lesion [
(Fig. 1). After the initial fork pause, the stalled CMGs
are unloaded and lesion bypass is initiated when the
leading strand of a single fork is extended to within 1
nucleotide of the ICL lesion [
]. Concurrent with
this, the structure-specific endonucleases localize to the
site of the ICL and promote dual incisions on either side
of the ICL, a process also referred to as “unhooking” of
the ICL . A number of endonucleases have been
implicated in the incision events of ICL repair including
the 3′ flap endonuclease XPF-ERCC1, MUS81-EME1,
FAN1, the 5′ flap endonuclease SLX1 and the
scaffolding protein SLX4 [
]. TLS polymerases then fill in
the gap at the site of the DNA incision. TLS
incorporates a nucleotide across the ICL lesion by utilizing the
error-prone DNA polymerase ζ. This allows the leading
strand to be extended and ligated to the first
downstream Okazaki fragment [
12, 45, 46
]. Finally, the broken
sister chromatids generated by incision generates a DSB
in the DNA that is repaired by RAD51-mediated HR
utilizing the intact sister chromatid as a homology donor
] (Fig. 1).
In recent years the role of FA network of proteins in
replication-dependent ICL repair has been the subject of
intense research in many laboratories. In this section, we
summarize the functions of the FA network of proteins
in ICL repair and discuss the mechanisms by which they
function in the repair of ICLs by promoting HR.
Overview of the Fanconi Anemia DNA damage response pathway
The FA pathway is a nuclear multi-protein network
comprised of 20 complementation groups and associated genes.
Interestingly, 19 of the 20 genes of this network are
autosomally inherited with the notable exception of FANCB.
FANCB is localized on the X chromosome and its
mutation has only been observed in males [
]. The genes were
identified by methods such as, complementation analysis
of cell lines from different FA patients, positional cloning,
biochemical purification, and by sequencing candidate
]. The proteins encoded by these genes make
Fig. 1 (See legend on next page.)
(See figure on previous page.)
Fig. 1 A model for the DNA interstrand crosslink (ICL) repair: Crosstalk between the Fanconi Anemia (FA) pathway, translesion synthesis (TLS) and
homologous recombination (HR). a Certain endogenous, environmental sources and chemotherapeutic agents inflict damage to the DNA
forming adducts between each DNA strands creating inter-strand crosslinks. b Two replication forks converge at the DNA ICL covalently
linking the Watson and Crick strands of the DNA. The replication machinery encounters the DNA lesion at the fork leading to fork stalling. c The
FA core complex detects the stalled replication fork, assembles on the DNA lesion and initiates checkpoint response by activating ATR, which
in turn phosphorylates multiple FA proteins. This triggers the ubiquitin ligase activity of FANCL resulting in monoubiquitination of FANCD2
and FANCI. d The FANCD2-FANCI heterodimeric complex is recruited to the ICL site. This further recruits downstream nucleases, in particular
structure specific endonucleases like SLX4 (FANCP), ERCC1-XPF, FAN1 and MUS81-EME1 to coordinate nucleolytic incisions flanking the ICL.
The incisions unhook the ICL leaving crosslinked nucleotides tethered to the complementary strand. FAAP20 interacts with the FA core
complex and binds to monoubiquitinated REV1. This catalyze TLS-dependent lesion bypass across the adduct, mediated by specialized TLS polymerases
such as REV1 and Polζ. This restores the integrity of the template strand required for the progression of the nascent leading strand. e DSB generated after
nucleolytic incisions serves as a suitable substrate for repair by the HR pathway. Downstream FA proteins promote RAD51-dependent strand invasion
forming the synaptic filament. Branch migration and intermediates containing Holliday junctions are formed. f The resulting double Holliday junction is
resolved by HR specific nucleases, HR repair is completed and the integrity of the DNA is restored
up the FA network of proteins that cooperate in the DNA
damage response (DDR) for the cellular resistance to ICLs
(Fig. 1). These proteins have been placed into three groups
based on the stage of ICL repair they participate in .
Group I, also referred to as the FA core complex consists
of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG,
FANCL, FANCM and FANCT (UBET2) along with five
additional proteins that associate with the FA core
complex, including FAAP100, FAAP24, FAAP20, and the
histone fold dimer proteins MHF1 and MHF2 [
Group II also referred to as the ID complex consists of
FANCD2 and FANCI proteins [
]. Group III proteins
include the DNA repair factors including HR proteins
BRCA2 (FANCD1), BRIP1 (FANCJ), PALB2 (FANCN),
RAD51C (FANCO), RAD51 (FANCR), SLX4 (FANCP),
BRCA1 (FANCS), and XRCC2 (FANCU), TLS gene REV7
(FANCV) and DNA endonuclease XPF (FANCQ) [
]. Some patients with FA-like cellular phenotypes are yet
to be assigned a FA-subtype indicating that additional FA
or FA-associated genes are yet to be identified [
The FA Core complex
FANCM is a DNA translocase which together with
Fanconi anemia-associated protein 24 (FAAP24), FAAP 100
and the histone fold proteins MHF1 (FAAP16 or CENPS)
and MHF2 (FAAP10 or CENPX) is responsible for lesion
recognition and recruitment of the core complex which
comprises of FANCA, FANCB, FANCC, FANCE, FANCF,
FANCG, FANCL, FANCT, and FAAP20 to the ICL site
] (Fig. 1). It is important to note that
recruitment of FANCM to ICLs is dependent on its
phosphorylation by the ataxia telangiectasia and RAD3-related (ATR)
checkpoint kinase . Once recruited to the site of
damage, the FA core complex serves as a multi-subunit
ubiquitin E3 ligase for two other FA proteins, FANCD2 and
]. FANCD2 is phosphorylated in an
ATRdependent manner which is essential for FANCD2
monoubiquitination and the establishment of the intra-S-phase
checkpoint response [
]. Phosphorylation of FANCI is
also essential for the monoubiquitination and localization
of the FANCD2–I heterodimeric complex to DNA
damage sites [
]. The phosphorylated FANCD2–I complex is
subsequently monoubiquitinated by the FA core complex
through its catalytic subunits, FANCL (the E3 ligase) and
UBE2T (the ubiquitin E2 ligase also known as FANCT)
]. Ubiquitinated PCNA also stimulates FANCD2
and FANCI monoubiquitination in vitro [
ubiquitinated FANCD2–I complex is then recruited to
chromatin by UHRF1 (ubiquitin-like with PHD and RING
finger domains 1) protein that is involved in ICL sensing
Ubiquitination of FANCD2–I is a reversible regulatory
modification. Deubiquitination of the FANCD2–I
complex is required to release FANCD2 from the DNA
repair complex crucial for subsequent repair steps to
complete ICL repair [
]. The deubiquitination of
FANCD2–I relies on USP1 (ubiquitin carboxy-terminal
hydrolase 1) in conjunction with UAF1 (USP1-associated
factor 1) [
DNA incision and Translesion repair
Ubiquination of the FANCD2–I complex is crucial for the
recruitment of nucleases to the site of the ICL to
orchestrate nucleolytic incision of the ICL. This facilitates
‘unhooking’ of the ICL from one of the two parental DNA
strands to uncouple one sister chromatid from the other
] (Fig. 1). FANCD2-Ub recruits the nuclease scaffold
protein SLX4 (FANCP) by an interaction with
ubiquitinrecognizing UBZ4 motif [
]. SLX4 (FANCP)
functions as a molecular platform to coordinate, recruit and
activate other structure-specific endonucleases like
XPFERCC1, MUS81-EME1 and SLX1 to aid ICL repair
]. Interestingly, in vitro studies have shown
that XPF–ERCC1–SLX4 complex is the essential nuclease
for ICL unhooking whereas MUS81-EME1, SLX1 and
FAN1 (Fanconi-associated nuclease 1, another
structurespecific nuclease that acts in a FANCP independent
manner) possess redundant ICL processing activities [
It is important to note that in human cells, the
recruitment of XPF at sites of ICL damage is dependent on the
structural protein nonerythroid αspectrin (αIISp) during
the S-phase of the cell cycle [
]. After unhooking of
the ICL lesion, ubiquitinated PCNA and the FA core
complex recruit translesion synthesis polymerases to
coordinate the next step of ICL repair. Translesion DNA
polymerases such as REV7 (FANCV), polymerase ζ and
polymerase η fill the single-strand DNA (ssDNA) gaps
resulting from ICL unhooking. Translesion DNA
polymerases have larger binding pockets compared to
replicative polymerases and can accommodate bulky ICL
adducts thereby incorporating nucleotides opposite to the
ICL and filling the DNA gap [
Downstream Effector complex
In addition to ssDNA gaps formed in one strand of the
double helix, unhooking results in the formation of DSB
afflicting both strands. Repair of DSBs relies on the HR
pathway (Fig. 1). Consistent with this, cells deficient in
HR proteins display hypersensitivity to ICL agents [
]. FA proteins involved in HR are not required for
FANCD2–I monoubiquitination suggesting they
function downstream of the FANCD2–I complex. Several FA
factors have been shown to promote different stages of
HR . BRCA2 (FANCD1), FANCO (RAD51C) and
PALB2 (FANCN) help load RAD51 onto ssDNA by
displacing RPA, which specifically promotes
RAD51dependent nucleofilament formation and also stimulates
RAD51-dependent strand invasion of a homologous
DNA template [
]. End resection is a key step in
DSBR and initiates HR. FANCD2 and BRCA1 (FANCS)
promote the recruitment of the resection factor CtIP at
the site of DSBs to initiate HR [
]. FANCC has
been implicated in inhibiting non-homologous end
joining (NHEJ) factors from accessing the DSB ends thus
preventing NHEJ and thereby promoting HR .
FANCJ’s (BRIP) 5′ to 3′ helicase activity has been shown
to unwind D-loops and may be involved in resolving
RAD51 nucleofilaments [
Regulation of the FA network of proteins
ICL repair is a highly complex process involving the FA
pathway as well as other repair pathways that needs to be
tightly controlled. Post-translational modifications (PTMs)
and protein-protein interactions are crucial for the
regulation of this process. ATR plays a major regulatory role in
the activation of the FA pathway. This kinase is
responsible for the phosphorylation of the FANCD2-I
heterodimer in the S-phase, which is indispensible for efficient
FANCD2 ubiquitination and focus formation [
]. ATR also phosphorylates FANCA, FANCG and
FANCM to promote efficient crosslink repair [
Chk1 also negatively regulates the FA pathway by
phosphorylating FANCE to trigger its proteasomal
]. Ubiquitination of various FANC proteins
is crucial for the regulation of the FA pathway.
Monoubiquitination of the FANCD2-I complex by the
FANCLUBE2T is crucial for recruitment of the core complex to
damaged DNA [
]. Additionally, ubiquitination of
effector proteins like FANCN, FANCS and FANCG have
been implicated in the regulation of ICL repair [
Deubiquitination of FANCD2 and FANCI by the
constitutively active deubiquitinating complex UAF1-USP1 keeps
the pathway turned off unless required [
]. Upon DNA
damage, the activity of UAF1-USP1 is repressed either by
proteosomal degradation of USP1 or by transcription
repression of the USP1 gene [
]. Finally, SUMOylation
plays a pivotal role in the regulation to FA-mediated ICL
]. SUMOylation of FANCD2 and FANCI by
PIAS1/4 and UBC9 promotes polyubiquitination of the
complex, which in turn promotes dissociation of FANCD2
and FANCI from chromatin [
FA factors as therapeutic targets in cancer
A hallmark of cancer cells is genome instability. This can
be attributed to a failure of the DNA repair machinery,
which essentially acts as a tumor suppressor network to
preserve genome integrity and prevent malignancy. The
link between FA and cancer predisposition has been well
established with FA patient populations exhibiting a wide
range of cancers [
]. Almost 25% of FA patients develop
]. Although the most common
malignancies are either hematologic, like myelodysplastic
syndrome and AML or solid tumors, particularly squamous
cell carcinomas of the head and neck [
], recently FA
proteins mutations have been reported in familial and
sporadic cancers outside the FA patient population [
For instance, FANCD1 mutations have been associated
with ovarian, breast, prostate, stomach and pancreatic
]. FANCL mutations have been associated
with lung cancer, pancreatic cancer, breast cancer and
]. FANCD2 mutations have been
associated with breast cancer . FANCN mutations have
been reported in prostate and breast cancer [
and FANCG have also been implicated in pancreatic
cancer, breast cancer and leukemia [
124, 127, 128
Leveraging synthetic lethal interactions with the FA pathway for cancer therapeutics
A major drawback of chemotherapy lies in the fact that
it is not selective, i.e., it kills both cancer cells and
normal cells indiscriminately. However, inactivation/defects
in DNA repair pathways can make cancer cells
overdependent on a compensatory DNA repair pathway for
survival. Current approaches for cancer therapy that rely
on inhibiting the intact functional DNA repair pathways
by using a synthetic lethal approach can provide a
therapeutic strategy for specific killing of such tumors.
Two genes are said to be in a synthetic lethal
relationship if a mutation in either gene alone is not lethal but
simultaneous mutations are lethal [
]. A new
approach is directed at exploiting the synthetic lethality of
cancer cells that are defective in the FA pathway .
The best example of the therapeutic potential of the
synthetic lethality approach is development of
poly(adenosine diphosphate [ADP]–ribose) polymerase 1 (PARP1)
inhibitors to treat breast and ovarian cancers carrying
mutations in the tumor-suppressor genes BRCA1 or
] (Fig. 2). Recognition of DNA breaks by
PARP1 is one of the earliest events in DSBR. Once a DNA
strand break is formed, PARP1 binds to the broken DNA
ends and facilitates chromatin decondensation at the
break site . This allows repair enzymes to access the
damaged DNA sites [
]. Inhibition or deletion of PARP1
leads to inactivation of the single strand break repair
(SSBR) pathways including NER, base excision repair
(BER), mismatch repair (MMR) which leads to the
accumulation SSBs which may subsequently lead to the
formation of DSBs [
]. BRCA1 and BRCA2 are also key
participants in HR. In normal cells, loss of activity of
PARP1 enzyme induces high levels of DSBR through the
HR pathway during the S-phase of the cell cycle. Cancer
cells that are defective in HR are selectively sensitive to
PARP inhibition due to the simultaneous loss of two DNA
repair pathways. Thus, treating cells carrying BRCA1 or
BRCA2 mutations with small-molecule inhibitors of
PARP1 are lethal as the cells are deficient in DSBR. This
results in targeted killing of the cancerous cells, while cells
with intact HR can repair the damage and survive [
Synthetic lethal interactions with the FA pathway for the
development of inhibitors have been explored. A
siRNAbased synthetic lethal screening identified several genes
including ATM, PARP1, CDK1, NBS1, and PLK1 that
showed synthetic lethal interactions with FANCG,
indicating that these genes could be targeted concomitant with a
FA pathway inhibitor [
]. Since ATM deficiency has
been reported in triple- negative breast cancer and several
types of hematological malignancies like mantle cell
lymphoma, chronic lymphocytic leukemia, and acute
lymphoblastic leukemia [
], the FA pathway
inhibitor could have immense therapeutic potential. CHK1
inhibition has also been shown to be synthetically lethal with
FANCA deficiency following cisplatin treatment .
Several small molecule inhibitors have been identified
that inhibit specific components of the FA pathway.
This in turn leads to inhibition of FANCD2 foci
formation and abrogation of the FA pathway. For example,
wortmannin (inhibits ATR kinase), H-9 (inhibits several
kinases including protein kinase A, G, and C),
alsterpaullone (inhibits cyclin-dependent kinase 1 and 5),
phenylbutyrate (inhibits FANCS) and curcumin (inhibits
FANCF) are some of the small-molecule inhibitors of the
FA/BRCA pathway that have already been identified by
high-throughput screen using human cells and are now in
various stages of subsequent validation [
Bortezomib, the natural compound curcumin and its analogs
such as EF24 and 4H-TTD and MLN4924 have been
shown to impair FANCD2 activation and sensitize cancer
cells to ICL-inducing agents [
18, 139, 141
inhibitors like C527, pimozide and GW7647 affect the
ubiquitin-deubiquitination cycle of FANCD2 leading to
the selective inhibition of the FA pathway [
Understanding the mechanism by which these compounds
chemically inhibit the FA/BRCA2 pathway is crucial for
translating this research from the laboratory to the clinic.
For instance, phenylbutyrate sensitizes head and neck
cancer cells to cisplatin by specifically attenuating FANCS
thereby inhibiting FANCD2 foci formation and abrogating
the FA/BRCA pathway . This observation makes
phenylbutyrate an excellent candidate for sensitizing
cisplatin-resistant head and neck tumors in a clinical
]. Curcumin (diferuloylmethane), a
lowmolecular-weight polyphenol and a component in the
spice turmeric inhibits FANCF [
]. Since FANCF acts
upstream in the FA/BRCA pathway, inhibition of FANCF
attenuates monoubiquitination of FANCD2 and FANCD2
foci formation [
]. In ovarian and breast tumor cell
lines, curcumin-mediated inhibition of the FA/BRCA
pathway sensitizes tumor cells to cisplatin by inducing
apoptotic cell death. This opens up the possibility that
curcumin could be used to sensitize cisplatin-resistant
ovarian and breast tumors in the clinic. The precise
inhibition of the FA pathway in combination with DNA repair
inhibitors could increase the efficacy of chemotherapy and
improve current cancer treatment regimens.
Understanding the molecular details of the DNA damage
response is essential for advancing cancer research. Due
to the critical importance of the FA network in
maintaining genome stability and the current limitations in treating
FA patients in the clinic, a large body of research has been
directed to this subject. The FA pathway plays a central
role in ICL repair during which the FA proteins function
to coordinate NER factors, TLS polymerase, HR factors
and checkpoint kinases to ensure genome stability. In the
absence of a functional FA pathway, cells are predisposed
to spontaneous and DNA damage-induced chromosomal
breaks. More research into the FA DNA repair pathway
will identify novel factors that can be specifically inhibited.
Such targeted modulation of the FA pathway by exploiting
synthetic lethal relationships may play an important role
for the development of new cancer treatments and
potential development of personalized therapies.
AML: Acute myelogenous leukemia; ATR: Ataxia telangiectasia and
RAD3related; CDDP: Chemotherapeutic agent cisplatin; DDR: DNA damage
response; DEB: Diepoxybutane; DSB: Double strand break; DSBR: Double
strand break repair; dsDNA: Double-strand DNA; FA: Fanconi Anemia;
FAN1: Fanconi-associated nuclease 1; HR: Homologous recombination;
ICLs: Interstrand DNA crosslinks; MMC: Mitomycin C; NER: Nucleotide excision
repair; PTMs: Post-translational modifications; ssDNA: Single-strand DNA;
TLS: Translesion synthesis; UAF1: USP1-associated factor 1; UHRF1:
Ubiquitinlike with PHD and RING finger domains 1; USP1: Ubiquitin carboxy-terminal
We apologize to those colleagues whose work has not been cited due to
Availability of data and materials
SB and SN were involved in the conception, design and drafting of the
manuscript. Both authors read and approved the final manuscript.
Ethics approval and consent to participate
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