Expanded roles of the Fanconi anemia
pathway in preserving genomic stability
Younghoon Kee and Alan D. D’Andrea1
Department of Radiation Oncology and Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston,
Massachusetts 02115, USA
Studying rare human genetic diseases often leads to a
better understanding of normal cellular functions. Fan-
coni anemia (FA), for example, has elucidated a novel
DNA repair mechanism required for maintaining geno-
mic stability and preventing cancer. The FA pathway, an
essential tumor-suppressive pathway, is required for pro-
tecting the human genome from a specific type of DNA
damage; namely, DNA interstrand cross-links (ICLs). In
this review, we discuss the recent progress in the study
of the FA pathway, such as the identification of new
RAD51C and FAN1 (Fanconi-associated nuclease 1) as
new FA pathway-related proteins. We also focus on the
role of the FA pathway as a potential regulator of DNA
repair choices in response to double-strand breaks, and its
novel functions during the mitotic phase of the cell cycle.
and theidentification of
The basic Fanconi anemia (FA) pathway
FA is a genomic instability syndrome characterized by
bone marrow failure, developmental abnormalities, and
increased incidence of cancers (D’Andrea and Grompe
2003; Moldovan and D’Andrea 2009). At the cellular
level, FA cells display increased chromosomal aberra-
tions, particularly radials, and hypersensitivity to DNA
interstrand cross-link (ICL) agents. DNA ICLs are among
the most deleterious DNA lesions, since they block DNA
replication and transcription. DNA ICLs can be caused by
endogenous sources such as nitrous acid and aldehydes,
or exogenous agents such as Cisplatin and its derivatives.
Because of its essential functions in preserving genomic
stability, the FA pathway provides a unique model for
studying eukaryotic DNA repair and DNA damage re-
sponses, particularly against DNA ICLs.
FA is a genetically heterogeneous disease, caused by
mutations in at least 13 distinct genes (FANCA, FANCB,
FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG,
FANCI, FANCJ, FANCL, FANCM, and FANCN). All 13
gene products are believed to function in a common DNA
repair signaling pathway, the FA pathway, which closely
cooperates with other DNA repair proteins for resolving
DNA ICLs during replication (Fig. 1). A central event in
the pathway is the monoubiquitination of FANCD2 and
FANCI upon DNA damage, which is mediated by a group
of upstream FA proteins (FANCA, FANCB, FANCC,
FANCE, FANCF, FANCG, FANCL, and FANCM) that
are assembled into a large nuclear E3 ubiquitin ligase
complex, termed the ‘‘FA core complex’’ (Kennedy and
D’Andrea 2005; Wang 2007). The monoubiquitinated
FANCD2/FANCI heterodimer was shown to play multi-
ple roles in the pathway (Knipscheer et al. 2009), and to
functionally interact with downstream FA proteins such
as FANCD1 (or BRCA2), FANCN, and FANCJ, and their
associated protein, BRCA1. In addition to these core FA
proteins, there are several FA pathway-associated pro-
teins whose functions are critical to the pathway; how-
ever, mutations have not been found in the corresponding
genes in FA patients. These include Fanconi-associated
protein 24 (FAAP24), FAAP100, FANCM-associated his-
tone fold protein 1 (MHF1), and MHF2 (Ciccia et al. 2007;
Ling et al. 2007; Singh et al. 2010; Yan et al. 2010). All of
these proteins are required for efficient activation of
FANCD2 monoubiquitination. FAN1 (Fanconi-associ-
ated nuclease 1), the most recently identified FA-associ-
ated protein, was shown to provide the cryptic nuclease
activity during the ICL repair (Kratz et al. 2010; Liu et al.
2010; Mackay et al. 2010; Smogorzewska et al. 2010).
Although not required for FANCD2 monoubiquitination,
it binds to the monoubiquitinated FANCD2 and mediates
the critical downstream functions, possibly via restructur-
ing thedamagedDNA. The activatedFA pathway must be
inactivated for completion and recycling of the functional
pathway, and this event is regulated by the USP1/UAF1
deubiquitinating enzyme complex, which deubiquitinates
FANCD2 and FANCI (Nijman et al. 2005; Cohn et al.
2007; Smogorzewska et al. 2007). Disruption of the USP1/
UAF1 complex leads to elevated levels of FANCD2/
FANCI ubiquitination and DNA repair defects, suggesting
a failure in the completion of the FA pathway.
In addition to these FA or FA-associated proteins, there
are other DNA repair factors—specifically, DNA damage
checkpoint proteins such as ATR, CHK1, and g-H2AX—
that cooperate with the FA pathway in response to DNA
[Keywords: Fanconi anemia; DNA repair; interstrand cross-link (ICL);
homologous recombination (HR); nonhomologous end-joining (NHEJ);
E-MAIL email@example.com; FAX (617) 632-5757.
Articleis online at http://www.genesdev.org/cgi/doi/10.1101/gad.1955310.
1680GENES & DEVELOPMENT 24:1680–1694 ? 2010 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/10; www.genesdev.org
damage (Andreassen et al. 2004; Wang 2007; Moldovan
and D’Andrea 2009). These checkpoint proteins preserve
genomic stability by arresting the cell cycle after DNA
damage. Cells deficient in ATR kinase, a master regulator
of S-phase checkpoint, are impaired in damage-inducible
monoubiquitination of FANCD2, and are hypersensi-
tive to ICLs (Andreassen et al. 2004). Many of the FA
proteins are direct substrates of ATR or its effector
kinase, CHK1—including FANCD2, FANCI, FANCA,
and FANCE (Pichierri and Rosselli 2004; Smogorzewska
et al. 2007; Wang et al. 2007; Ishiai et al. 2008; Collins
et al. 2009)—and these phosphorylation events are re-
quired for a functional FA pathway and ICL repair. The
FANCM and FAAP24 complex is also required upstream
for efficient ATR-mediated checkpoint control (Collis
et al. 2008; Luke-Glaser et al. 2010; Schwab et al. 2010).
Recently, FANCJ was also shown to regulate the ATR-
dependent checkpoint (Gong et al. 2010). Taken together,
these studies suggest that the FA pathway is closely
interconnected with other DNA damage responsesignals.
The precise molecular function of individual FA proteins
in repairing DNA and communicating with other DNA
damage responses remains largely unknown. However,
recent studies have provided unique insights to the field.
These findings may potentially bring venues for novel
therapeutic approaches for treating both FA patients and
FA pathway-deficient tumors.
FANCM plays multiple distinct roles during ICL repair
While facilitating DNA cross-link repair, the FA pathway
must coordinate other DNA damage-responsive events to
(A) Activation of the FA pathway. DNA ICL is
directly recognized by FANCM–FAAP24–MHF pro-
tein complex. This complex recruits the FA core
complex by direct interaction between FANCM and
FANCF. The recruited FA core complex, containing
a PHD E3 ubiquitin ligase domain in the FANCL
subunit, subsequently monoubiquitinates its two
substrates, FANCD2 and FANCI, on chromatin.
The monoubiquitinated FANCD2–FANCI becomes
an active form, recruits newly identified nuclease
FAN1 or interacts with a series of DNA repair pro-
teins (including BRCA1, PALB2 ½FANCN?, BRCA2,
and FANCJ ½BACH1/BRIP1?) at the damaged sites,
and facilitates downstream repair pathways. RAD51C,
a newly identified FA-like protein, may have a func-
tional interaction with FANCD2 at this step.
FANCD2–FANCI probably also recruits other nu-
cleases and TLS polymerases to process the ICL (not
shown). The new players in the FA pathway de-
scribed in the text are highlighted in dashed lines.
(B) The FA pathway cross-talks with ATR–CHK1
checkpoint proteins. ATR and its effector kinase,
CHK1, are required for damage-inducible activation
of the FA pathway. ATR–CHK1 phosphorylates (red
arrows) multiple FA and FA-associated proteins,
including FANCA, FANCE, FANCD2, FANCI, and
BRCA1. FANCM is also phosphorylated upon DNA
damage by an unknown kinase. In turn, the stability
and activity of ATR–CHK1 are promoted (black
arrows) by the FANCM–FAAP24 heterodimer and
FANCJ by independent mechanisms. FANCM also
mediates the formation of the BRAFT complex,
which contains the FA core complex members and
the BLM complex containing Topo IIIa and RMI1/2
A schematic model for the FA pathway.
Expanded roles of the FA pathway
GENES & DEVELOPMENT1681
stabilize stalled replication forks, to convey signals to
DNA checkpoint pathways, and to facilitate recovery of
replication forks. These events are largely coordinated by
FANCM, a unique member of the FA pathway that plays
distinct roles in checkpoint activation, chromatin remod-
eling, and ICL repair. FANCM contains a DEAH-type
ATPase-dependent helicase domain, and it is one of the
only two FA proteins with recognizable enzymatic activ-
ities, together withthe helicase activity of FANCJ(Whitby
2010). FANCM is evolutionarily well conserved, as it is
the only FA protein that has apparent orthologs in yeast
(MPH1 in Saccharomyces cerevisiae, and Fml1 in Schizo-
saccharomyces pombe) and archaebacteria (Hef) (Meetei
et al. 2005; Sun et al. 2008). Also, FANCM is one of only
two proteins in the human genome known tocontain both
a helicase/ATPase domain and an endonuclease domain in
a single polypeptide, the other being ERCC4 (XPF) (Ali
et al. 2009). The identity of FANCM as a bona fide FA
protein is still in question, since the only known FANCM-
deficient patient cell line, EUFA867, harbors an additional
mutation in FANCA, and the full correction of the FA
phenotype requires ectopic expression of both FANCM
and FANCA (Singh et al. 2009). However, FANCM clearly
plays critical roles in the FA pathway, and functions
cooperatively with other FA core members. For instance,
in DT40 cells, a double knockout of FANCM and FANCC
exhibits ICL hypersensitivity similar to individual gene
knockouts, indicating that FANCM and FANCC are
epistatic (Mosedale et al. 2005). One role of FANCM in
the FA pathway is to sense damaged DNA and recruit the
FA core complex. FANCM was originally identified as
a subunit of the FA core complex (Meetei et al. 2005), but
its cellular distribution is distinct from the other FA core
members. FANCM forms a heterodimeric complex with
FAAP24, a protein sharing high similarity to the C ter-
minus of FANCM and also containing an endonuclease-
like domain (Ciccia et al. 2007). In vitro, the FANCM/
FAAP24 complex binds directly to DNA structures that
resemble stalled replication forks. Also, the FANCM/
FAAP24 complex binds constitutively to chromatin,
whereas other FA core proteins become enriched in the
chromatin fraction only after DNA damage (Meetei et al.
2005; Mosedale et al. 2005; Kim et al. 2008). Furthermore,
depletion of FANCM results in impaired localization of
the FA core proteins. Taken together, these results suggest
a model in which the FANCM/FAAP24 complex serves as
a sensor that recognizes the DNA lesion and subsequently
recruits the FA core complex to induce monoubiquitina-
knockout mice are still capable of inducing residual
monoubiquitinated FANCD2 (Bakker et al. 2009). Accord-
ingly, there may be a FANCM-independent recruiting
mechanism for the FA core complex, or there may be
a basal-level interaction between the FA core complex and
FANCD2/I in the absence of FANCM/FAAP24.
FANCM also has unique features that are not shared by
other FA core complex members. FANCM knockout mice
display typical FA phenotypes (e.g., hypersensitivity to
ICL, chromosomal breakage, and increased G2/M arrest),
but also exhibit additional atypical phenotypes such as
a low female ratio and increased cancer-related death
(Bakker et al. 2009). FANCM-deficient cells are also hy-
persensitive to camptothecin, a topoisomerae I (Topo I)
inhibitor that induces replication fork arrests, followed
by DSB generation (Singh et al. 2009).
Unlike other FA subtypes, FANCM-deficient cells ex-
hibit elevated frequency of sister chromatid exchange
(SCE). Bloom’s syndrome, a rare genetic disorder caused
by a single mutation in the RecQ family helicase BLM,
also exhibits elevated SCE, among other phenotypes that
and increased hematological cancers (Liu and West 2008).
Interestingly, the overlapping phenotypes of FA and BLM
could be linked molecularly to the ICL-induced assembly
of a supercomplex, termed BRAFT (BLM, RPA ½replication
protein A?, FA, and Topo IIIa), that contains the members
of the FA core complex, BLM, and its associated proteins
(Meetei et al. 2003). A recent study provided a direct
demonstration that FANCM serves as an adapter between
the FA proteins and the BLM complexes (Deans and West
2009), and it was demonstrated that the elevated fre-
quency of SCE is due to the failed assembly of the BRAFT
through FANCM. Together, FANCM plays a critical role
in mediating the cross-talk between the FA proteins and
BLM complex, particularly in response to ICLs, and this
could be the fundamental link for the overlapping clinical
phenotypes between the two genetic disorders.
One of the FA-independent functions of FANCM is its
ability to activate DNA damage checkpoints. FANCM
and FAAP24, but not other FA proteins, were shown to
associate physically with a complex containing ATR–
HCLK (HCLK2 is a stabilizer and signaling mediator of
ATR), and thus are required for proper activation of the
ATR-mediated S-phase checkpoints in response to repli-
cation stress (Collis et al. 2008). Depletion of FANCM–
FAAP24 leads to uninhibited cell cycle progression
through G2/M phases. This function is dependent on its
ATPase activity, which is dispensable for its monoubi-
quitination of FANCD2/FANCI, further suggesting the
existence of at least two separate functions. One mech-
anism for ATR activation is the ability of FANCM to
retain TOPBP1, a stimulator of ATR kinase activity, in
the chromatin (Schwab et al. 2010). Although this check-
point-activating function is not involved directly with
the FA pathway, FANCM-mediated ATR activation may
provide an indirect mechanism for further activating the
FA pathway (see Fig. 1B). Also, more recent studies
indicate that FANCM/FAAP24 can activate a specific
ICL checkpoint response by enhancing RPA binding at
the site of the ICL (AD D’Andrea, unpubl.).
In addition to checkpoint signaling, FANCM has a role in
remodeling replication forks. In vitro, FANCM binds DNA
structures that mimic replication forks and Holliday junc-
tions, and moves the junction points through its branch
migration activity in an ATPase-dependent manner (Gari
et al. 2008b). This activity is also not coupled to the FA
pathway, since the ATPase activity is dispensable for
FANCD2/I monoubiquitination (Xue et al. 2008). A sub-
to fork reversal during replication blockage, and suggested
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Kee and D’Andrea
1694 GENES & DEVELOPMENT