©2005 LANDES BIOSCIENCE. DO NOT DISTRIBUTE.
FANCD2, which leads to the relocalization of FANCD2 to chromatin.14-17FA comple-
mentation groups that lack one of the members of the FA core complex, containing
FANC-A, -B, -C, -E, -F, -G, -L or -M, demonstrate deficient FANCD2 monoubiquitination
and thus, these proteins are considered to function upstream of FANCD2.10,18,19
Interestingly, the FA-D1 (BRCA2) and the FA-J (BACH1) complementation groups
appear to function downstream of FANCD2.7,9,11,15,20Unlike components of the FA core
complex, neither BRCA2 nor BACH1 are required for FANCD2 monoubiquitination.
[Cell Cycle 5:2, 164-167, 16 January 2006]; ©2006 Landes Bioscience
2006; Vol. 5 Issue 2
Sharon B. Cantor1,*
Paul R. Andreassen2
1Department of Cancer Biology; University of Massachusetts Medical School;
Women's Cancers Program; UMASS Memorial Cancer Center; Worcester,
2Division of Experimental Hematology; Cincinnati Children's Hospital Medical
Center; Department of Pediatrics; University of Cincinnati College of Medicine;
Cincinnati, Ohio USA
*Correspondence to: Sharon B. Cantor; Department of Cancer Biology; University
of Massachusetts Medical School; 364 Plantation St.; Worcester, Massachusetts
01605 USA; Tel.: 508.856.4421; Fax: 508.856.1310; Email: Sharon.Cantor@
Received 11/14/05; Accepted 11/16/05
Previously published online as a Cell CycleE-publication:
BACH1, FANCJ, BRIP1, BRCA1, BRCA2, Rad51,
Fanconi anemia, homologous recombination
We thank the UMASS Medical School and the
Mary Kay Ash Foundation (S.B.C), and a
Cincinnati Children's Hospital Medical Center
Trustee Grant (P.R.A.) for financial support.
Assessing the Link Between BACH1 and BRCA1 in the FA Pathway
The BACH1 helicase was initially identified by its direct binding to BRCA1 and, thus,
was linked to hereditary breast cancer. More recently, BACH1 was identified as the gene
defective in the J complementation group of Fanconi anemia (FA). FA is a multigenetic
disorder characterized by cellular sensitivity to crosslinkers and chromosome instability.
Because FANCD2 monoubiquitination is intact in BACH1 deficient cells, BACH1 appears
to act downstream in the FA pathway akin to BRCA2/FANCD1. Interestingly, while
BRCA1 has various interactions with FA proteins it has not been identified as an FA gene.
As the race to uncover the last few unknown FA complementation groups comes to an
end, future work will be required to uncover how these gene products function to combat
the effects of DNA damage and maintain genomic stability. In particular, it remains elusive
whether BRCA1 is functionally linked to the FA pathway through its interaction with
BACH1/FANCJ. This review focuses on a model for the connection of BRCA1 to BACH1
in the FA pathway. We predict that BRCA1 regulates the BACH1 helicase activity to
coordinate the timely displacement of Rad51 from nucleofilaments, promoting error free
repair and ultimately maintaining chromosomal integrity.
BACH1 was first identified as a BRCA1 binding protein through its direct interaction
with the BRCT repeats of BRCA1.1The BRCT repeats are critical for DNA repair and
tumor suppressor functions of BRCA1.2The identification of BACH1 mutations in two
hereditary breast cancer patients suggested that BACH1 is also a tumor suppressor.1These
breast cancer-associated BACH1 mutations disrupted or reduced BACH1 helicase activity
in vitro, further linking tumor suppression to BACH1 helicase activity.3The finding that
BACH1 binding to BRCA1 is not only direct, but also dependent on BACH1 phospho-
rylation at S990,4did little to dispense of the idea that BACH1 was simply another
BRCA1 interacting protein that potentially contributes to BRCA1’s overall DNA repair
With the finding that BACH1 is the Fanconi anemia (FA) gene product FANCJ,
researchers have recently pulled BACH1 out from the large shadow cast by BRCA1. Three
groups independently uncovered that BACH1 is the defective gene in the Fanconi anemia
FA-J complementation group.5-7At last, the finding that BACH1 is an FA gene solidifies
the notion that BACH1 is a tumor suppressor and worthy of attention.
Similar to other FA patients, FA-J patients are characterized by growth retardation,
bone marrow failure, radial ray defects, and a predisposition to leukemia and solid
tumors.6,8-10Notably, BACH1 deficient mammalian cells have many of the features of FA
cells, including extreme sensitivity to DNA interstrand crosslinking agents such as mito-
mycin C (MMC) and cisplatin,7,11but mild sensitivity to ionizing radiation (IR).12
Moreover, BACH1 deficiency results in crosslinker-induced chromatid breaks, and the
formation of tri- and quadri-radial chromosome species, as is observed in cells from FA
patients.7,10,11,13This chromosome instability can most likely be attributed to the inability
of BACH1 deficient cells to perform homologous recombination (HR) dependent DNA
The FA pathway is characterized by the DNA damage-induced monoubiquitination of
Cells from FA patients deficient for FANC- A, G, and D2 have
modest defects in DNA double-strand break-induced HR, as
compared to deficiency for BRCA2.21,22While the exact function of
the FA core complex, and more specifically of monoubiquitinated
FANCD2, in HR have not been determined, one possibility is that
monoubiquitinated FANCD2 may regulate BRCA2 function in
HR.15,23In fact, purified FANCD2 has a structure specific
DNA-binding activity for Holliday Junctions and DNA double
strand breaks,24both of which are resolved or repaired by HR.
Alternatively, the FA core complex and FANCD2 called an indirect
role in HR and a more direct function in other DNA repair path-
Using an I-SCE-I assay, we have found that suppression of
BACH1 generates a defect in DNA double-strand break-induced
HR.7This is not surprising considering that BACH1 directly binds
BRCA1,1which has an important role in HR.27Also, like
BRCA2/FANCD1, which is required for HR, BACH1 functions
downstream of FANCD2.7,9,11,15,20However, the mechanism by
which BACH1 participates in HR is not clear. A comparison of
suppression of other FA proteins and BACH1 using the same HR
assay should provide clues about the specific roles of each of these FA
proteins in HR. The finding that BACH1 is unnecessary for HR in
chicken DT40 cells11highlights the importance of comparing the
role of different FA proteins directly in the same system.
Now that BACH1 is in the spotlight, we must reevaluate whether
BACH1 and BRCA1 are functionally connected in HR and/or in
the FA pathway. In fact, one could argue that BRCA1 and BACH1
function separately in HR. In particular, a major difference between
BACH1 and BRCA1 deficient cells is that Rad51 foci are clearly
formed in BACH1 deficient cells, but not in BRCA1 deficient
cells.7,28,29At first glance, one might therefore predict that BRCA1
functions upstream of Rad51 and BACH1 functions downstream of
Rad51. However, we hypothesize, instead, that BACH1 and BRCA1
function together in the FA pathway to coordinate HR. This
hypothesis is based on the fact that BACH1 and BRCA1 share
common features and functions.
Depletion of either BRCA1 or BACH1 in the same genetic back-
ground in mammalian cells disrupts HR to a similar degree.7
Moreover, in response to MMC both proteins are critical for cellular
survival and the maintenance of chromosomal integrity.7
Importantly, the BRCT domain of BRCA1, which mediates binding
to BACH1, is required for BRCA1 function in DNA repair and
tumor suppression.2This suggests the possibility that BRCA1 may
function in the cellular response to MMC by binding to BACH1.
Likewise, it has been demonstrated that the function of BACH1 in
DNA repair is dependent upon its binding to BRCA1.1More
recently, we have shown that in response to IR, both proteins disperse
and reform foci in an almost identical pattern.12BACH1, similar to
BRCA1, colocalizes with γ-H2AX at both early and late times
post-IR. And similar to BRCA1,30BACH1 is phosphorylated in
response to multiple forms of DNA damage.12Finally, not only does
BRCA1 appear to play a role in localizing BACH1,1but BACH1
also appears to play a role in localizing BRCA1,12predicting that
BRCA1 and BACH1 function together.
While BRCA1 itself has not been implicated directly as an FA
complementation group, several lines of evidence suggest that BRCA1
may function in the FA-pathway. First, BRCA1 and FANCD2, or
components of the FA core complex, all have some role in
HR,22,26,27and are required for the maintenance of chromosomal
integrity and for resistance to MMC and other DNA interstrand
crosslinkers.10,26Second, BRCA1 associates with PA proteins such as
BRCA2/FANCD131and BACH1/FANCJ.1Lastly, BRCA1 coim-
munoprecipitates and colocalizes with FANCD2 following exposure
to DNA damage.18If BRCA1 functions in the FA pathway, it would
appear that BRCA1 functions downstream of FANCD2, since
FANCD2 is monoubiquitinated in cells depleted of BRCA1.7,32
In order to reconcile the requirement for BRCA1, but not
BACH1 in the assembly of DNA damage-induced Rad51 foci,7,28,29
as discussed above, we propose the following model. First, we suggest
that BACH1 functions downstream of Rad51 to release Rad51 from
DNA upon completion of HR. Second, we propose that BRCA1
regulates BACH1 helicase activity to prevent the untimely displace-
ment of Rad51 from DNA until HR is complete (Fig. 1). Therefore,
in the absence of BRCA1, BACH1 helicase activity would be unreg-
ulated and would be expected to lead to the uncontrolled and
untimely release of Rad51 from single-stranded the helicase DNA
filaments. Other helicases have been shown to displace proteins from
DNA and have set the precedent for this hypothesis. In particular,
SRS2 can remove Rad51 from DNA33and more recently the Pif1p
helicase was shown to remove telomerase from telomeric DNA.34
In our model, loss of BACH1 in BRCA1-deficient cells would
augment the ability of cells to survive after DNA damage. Such a
situation occurs in S. pombe cells lacking the Crb2 protein, which
appears to be a close analog of BRCA1. In mutant Crb2 cells, Rqh1
helicase is unregulated. Thus, in Crb2 null cells, DNA damage sen-
sitivity is partially rescued by loss of Rqh1 helicase.35Similarly, loss
of BRCA1 could lead to defects in repair and increased chromosomal
abnormalities as a result of unregulated BACH1 enzyme activity.
Unregulated BACH1 may generate open DNA structures more
vulnerable to illegitimate recombination or other adverse modifica-
tions. Thus, the DNA damage defects found in BRCA1 mutant cells
may actually be rescued by suppression of BACH1, similar to the
rescue of these cells by reconstitution with WT BRCA1.36,37
Furthermore, if loss of BRCA1 function leads to suppression of HR
due to unregulated BACH1 helicase activity, then restoring BACH1
regulation should at least partially rescue the HR defect. This model
is readily testable and, if confirmed, may aid in designing approaches
to combat loss of BRCA1 in breast cancer patients.
Alternatively, BRCA1 may not directly regulate BACH1 helicase
activity, but rather aid in loading BACH1 onto the appropriate DNA
substrate. BRCA1 binds branched DNA structures,38which could
facilitate the efficient loading of BACH1 onto HR intermediates. In
Assessing the Link Between BACH1 and BRCA1 in the FA Pathway
Figure 1. Model for the function of BRCA1 and BACH1 in HR. We propose
that BACH1 functions to displace Rad51 from DNA strands to complete the
HR process. To prevent untimely displacement of Rad51 from DNA strands,
BRCA1 keeps BACH1 helicase activity in check. BRCA2 is important for
loading Rad51 onto DNA strands.
166 Cell Cycle 2006; Vol. 5 Issue 2
fact, BACH1 efficiently unwinds a 5’ flap substrate, which partially
resembles a D-loop HR intermediate.39Perhaps in the absence of
BRCA1, BACH1 may displace the invading strand of a D-loop at
the inappropriate time and thereby disrupt HR.
Regardless of the specific roles of BACH1 and BRCA1 in HR,
the link between BACH1 and BRCA1 makes one wonder whether
BRCA1 is also an FA gene. The question is even more relevant given
that the other hereditary breast cancer associated gene, BRCA2, is
FANCD1.40Moreover, like BRCA2/FANCD1 and BACH1/FANCJ,
BRCA1 is required for HR,7,21,27and is not required for FANCD2
monoubiquitination,7,9,11,15,20,32and therefore appears to function
downstream of FANCD2. As mouse models have shown, BRCA1
and BRCA2 null mice are not viable.41However, truncations of
either BRCA1 or BRCA2 in mice result in a viable organism with a
predisposition to cancer.42,43This is consistent with the fact that
FA-D1 patients have biallelic mutations that can yield a partially
functional truncated BRCA2 protein.40Potentially, biallelic mutations
of BRCA1 that yield a partially functional BRCA1 protein could
likewise produce an FA variant. The fact that BRCA1 mutant mice,
including those with mutations of the BRCT domain, are viable42
suggests that an FA-like human is a possibility. Moreover, there are
similarities between FANCD2 null mice and BRCA1 mutant mice,
which further support this possibility. FANCD2 and BRCA1
mutant mice have a predisposition to carcinomas, including breast
cancer,42,44,45and compromised function of the p53 tumor suppres-
sor enhances tumor formation in both FANCD2 null and BRCA1
If our model is correct and BACH1 requires BRCA1 to function
properly in HR, then biallclic mutations dispupting the BRCT
domain of BRCA1 should present an FA-like phenotype given that
BACH1 would be unregulated. An FA patient with BRCA1 muta-
tions has not been identified, perhaps because such biallelic mutations
could be lethal due to toxicity from unregulated BACH1 helicase
activity. In fact, in tissue culture cells we cannot maintain unregulated
BACH1 expression, whereas depletion of BACH1 is maintained
readily (Cantor S, unpublished data).
It is important to note that mice with homozygous deletions for
FANC-A, -C, -G and -D2 are viable,44and BRCA1 or BRCA2
nullizygous mice are not.41Thus it appears that either BRCA1and
BRCA2 have more essential roles in the same pathway as these FA
proteins or that they have unique functions outside of the FA pathway.
Since BACH1 in chicken DT40 cells lacks the motif4required for
interaction with BRCA1 in mammalian cells,11it is possible that the
function of BACH1 and BRCA1 in the FA pathway is not universal
to all organisms. Perhaps BRCA1 has shared functions with the FA
pathway only in organisms in which it interacts with BACH1
through its BRCT domain.
In conclusion, we propose a model in which BACH1 and BRCA1
function together in the FA pathway at the same step in HR. If
further research supports this model, the next step will be to deter-
mine what other proteins function with BRCA1 and BACH1. A
mechanistic understanding of the role of these proteins in HR will
ultimately clarify how the cell responds to DNA damage to maintain
a stable genome, and why loss of these proteins leads to the genesis
of breast cancer and other malignancies.
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Assessing the Link Between BACH1 and BRCA1 in the FA Pathway