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Human Molecular Genetics, 2003, Vol. 12, Review Issue 1 R113-R123
DOI: 10.1093/hmg/ddg082
© 2003 Oxford University Press

Roles of BRCA1 in DNA damage repair: a link between development and cancer

Chu-Xia Deng* and Rui-Hong Wang

Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, 10/9N105, National Institutes of Health, Bethesda, MD 20892, USA

Received October 23, 2002; Accepted January 29, 2003


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUMMARY AND FUTURE ASPECTS
 REFERENCES
 
DNA damage causes devastating problems for developing organisms. Recent studies reveal that BRCA1 plays essential roles in homologous recombinational repair, non-homologous end joining, and nucleotide excision repair. BRCA1 mediates these functions by interaction with components of the DNA repair machinery and by regulating expression of genes that are involved in these DNA damage repair pathways. Consequently, the absence of BRCA1 results in accumulation of chromosome damage, cell cycle abnormalities and apoptosis, leading to developmental abnormalities and adult tumorigenesis. In this review, we discuss recent advances regarding our understanding of the functions of BRCA1 in DNA damage repair and cellular responses that link development and cancer.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUMMARY AND FUTURE ASPECTS
 REFERENCES
 
DNA damage occurs throughout the life cycle of an organism, and is caused by both exogenous and endogenous factors. The exogenous factors are mainly environmental DNA damaging agents, such as ionizing radiation (IR), ultraviolet rays (UV), air pollution, inhaled cigarette smoke, alkylating agents and chemotherapeutic drugs. The endogenous factors include water, reactive oxygen species and unavoidable errors of certain cellular processes, such as DNA duplication and meiotic recombination during gametogenesis. An organism faces overwhelming problems if its DNA damage is not quickly repaired. So far, over 100 genes have been found in human cells that are involved in five major DNA damage repair pathways (reviewed in 1). These include homologous recombinational repair (HRR), non-homologous end joining (NHEJ), nucleotide excision repair (NER), base excision repair (BER) and mismatch repair (MMR) (reviewed in 2–6).

The importance of DNA damage repair has been appreciated by phenotypic analysis of mutant mice generated by gene targeting, a powerful technique that specifically disrupts genes of interest in vivo (7). Numerous studies have revealed that the absence of a gene responsible for DNA damage repair frequently causes cell cycle arrest and apoptosis, which, in turn, triggers a series of physiological responses affecting development. Table 1 lists about 40 genes that are involved in DNA damage repair. Mutations of these genes result in various development abnormalities, including embryonic lethality, proliferation defects, genetic instability, organ and tissue malformation, and premature aging. Of note, some of these are well-known tumor suppressor genes whose mutations have been found in many types of human cancers. Consistently, many mutant mice that survive to adulthood unavoidably develop tumors at varying ages (Table 1). These observations provide a strong link between DNA damage repair, development and tumorigenesis.


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  		Table 1. Phenotypes of mice carrying targeted disruption of genes that are involved in DNA damage repair
 
The breast cancer associated gene 1 (BRCA1) was mapped in 1990 (8) and cloned four years later (9). Germline mutations of BRCA1 have been found to predispose women to breast cancer and ovarian cancer (reviewed in 10–12). BRCA1 contains 24 exons that encode a large protein of 1863 amino acids in humans (9) and 1812 amino acids in mice (13). Surprisingly, it was found that targeted disruption of Brca1 in mouse results in embryonic lethality that is accompanied by growth retardation, apoptosis, cell cycle defects and genetic instability (reviewed in 14). These observations, as well as growth abnormalities exhibited by the mutant cells, suggest that BRCA1 acts as a caretaker through its role in maintaining genome integrity, instead of directly inhibiting cell proliferation (reviewed in 15,16). It is now clear that BRCA1 plays a role in maintaining genome integrity, at least in part, through its roles in DNA damage repair. Mounting evidence has implicated BRCA1 in HRR, NHEJ and NER. As the involvement of BRCA1 in HRR has been reviewed extensively (17–20), we will mainly discuss recent advances regarding the roles of BRCA1 in NHEJ and NER pathways after briefly reviewing the roles of BRCA1 in development and cancer.

Developmental abnormalities in the absence of BRCA1
The involvement of Brca1 in mammalian development is well illustrated by phenotypic analyses of at least nine mouse strains carrying germline mutations of Brca1 (21–29). Apparently, Brca1 is critical for normal development, as most mutant strains exhibit an embryonic lethal phenotype due to cellular proliferation defects, genomic instability and developmental retardation, although the onset of lethality among these mutant embryos falls within a wide range from E6.5 to E18 (reviewed in 30). A portion of Brca1 mutant mice of two strains that carry hypomorphic mutations can survive to adulthood when they are either in a p53-null background (22) or 129, but not in a C57BL/6 background (31). The first hypomorphic allele carries a targeted deletion of Brca1 exon 11 (Brca1{Delta}11/{Delta}11), which is the largest exon and encodes over 60% of amino acids of the protein (9,32), and the second carries a truncation mutation missing the last 888 amino acids of Brca1. About 10–15% of Brca1{Delta}11/{Delta}11 embryos exhibited exencephally caused by failure of anterior neural tube closure. Interestingly, when the Brca1{Delta}11/{Delta}11 mutation is placed into a null mutation of Gadd45 (33), a downstream gene of Brca1 (34), over 80% of embryos doubly homozygous for both mutations were exencephalic, revealing a synergistic action between Brca1 and Gadd45 in controlling neurulation (X. Wang and C. Deng, manuscript in preparation).

The Brca1 gene is expressed in many adult tissues to varying levels (9,13). The embryonic lethality associated with germline mutations of Brca1 obscures the functions of this gene in postnatal development. It was shown that Brca1 is highly expressed in rapidly proliferating mammary epithelial cells during pregnancy and down-regulated during lactation. To study possible roles of Brca1 in the mammary cycle of development and neoplasia, mice were generated that carry a Brca1 conditional knockout allele (Brca1Co), and a Cre transgene under the control of the whey acidic protein (WAP) gene promoter or the MMTV-LTR, which are active in mammary epithelial cells (35,36). Analysis of mammary glands of Brca1Co/CoMMTC-Cre or Brca1Co/CoWAP-Cre mice revealed abnormal alveolization and decreased branch morphogenesis of mammary glands. These defects occurred as early as the first pregnancy and were associated with abnormally increased apoptosis in mutant epithelium, suggesting an important role of Brca1 in proper development of mammary epithelium.

A role for Brca1 in T cell lineage development has been assessed using a conditional kncok-out allele of Brca1 and an Lck-Cre transgenic mouse, which results in specific deletion of Brca1 Exon 5 and 6 in T cells (37). These mice displayed impaired thymocyte development, i.e. 90% depletion of the thymocytes, and defective maturation of CD4 and CD8 double negative thymocytes, with accumulated chromosome damage and abnormal cell death. Interestingly, overexpression of Bcl2, a cell death inhibitor, or a p53-/- mutation completely restored survival and development of Brca1{Delta}5-6 thymocytes, while a p21-/- mutation partially restored peripheral T cell development, although it did not restore thymocyte development. These observations suggest that the impaired T cell lineage development is more likely caused by activation of p53 mediated apoptotic pathway rather than the p53/p21 mediated cell cycle arrest.

BRCA1-associated tumorigenesis
BRCA1 is a well-established tumor suppressor gene, as its germline mutations predispose women to high risk of breast and ovarian cancers (10–12). Generation of mouse models for BRCA1 associated breast cancer should facilitate studies on mechanisms of tumorigenesis, chemoprevention and therapeutic treatment. As discussed earlier, most Brca1 mutant strains die during gestation, so only those carrying tissue specific or hypomorphic mutations survive to adulthood (22,31,38,39).

Studying mice with conditional disruption of Brca1 in the breast (Brca1Co/CoMMTV-Cre), Xu et al. (38) found that mammary tumorigenesis occurred at low frequency after long latency. The majority of the tumors also displayed alterations of p53 transcripts, implicating this tumor suppressor in Brca1-associated tumor formation. A noticeable finding is that, although introduction of a p53+/- mutation significantly accelerated tumorigenesis, mammary tumors still appeared in a stochastic fashion, suggesting the involvement of multiple factors in addition to p53. This is also reflected by the highly diverse histopathological patterns of mammary tumors (31,39). Consistently, expression studies revealed extensive genetic/molecular alterations, including overexpression of ErbB2, c-Myc, p27 and Cyclin D1 in the majority of tumors (39). Tumors from Brca1 conditional mice also exhibit a high degree of chromosome abnormality (39,40), which is one of the major characteristics of cancer cells. It facilitates carcinogenesis by increasing the chance of specific mutations responsible for malignant phenotypes. Chromosome abnormalities in most cases reflect impaired mitotic functions, including unequal distribution of chromosomes and failure of cytokinesis, leading to the formation of aneuploid cells. This is consistent with a view that the tumorigenesis displayed by Brca1 mutant mice is secondary to genome instability (16), which, in part, is contributed by the impaired DNA damage repair.

BRCA1 and NHEJ
NHEJ and HRR are two major pathways for repairing DNA double-strand breaks (DSBs). Differing from HRR, which faithfully repairs DNA damages, NHEJ is largely inaccurate as it involves reactions of junctions with no homology or microhomology of 1–10 bases within 20 bp of the ends (reviewed in 2,3). To address the role of Brca1 in NHEJ, Zhong et al. (41) established a pair of mouse embryonic fibroblasts (MEFs) carrying a p53-null ( p53-/-) or Brca1-null and p53-null (Brca1-/-p53-/-) double mutations. Three independent in vivo approaches were carried out using these cells. The first approach employed a reporter plasmid, pGL2, in which expression of a luciferase gene requires precise end joining. The plasmid contains two unique restriction sites, HindIII and EcoRI. HindIII cleaves at the linker region between promoter and coding sequence. Any end-joining activity accompanied by small deletions or insertions would not affect the expression of the luciferase gene and could be considered an overall end-joining activity. EcoRI is located in the coding region of the luciferase gene and only precise end joining would restore the original sequence upon its digestion. The relative end-joining efficiency was calculated by comparing luciferase activity expressed in MEFs transfected with HindIII-or EcoRI-digested plasmid with that of MEFs transfected with the uncut plasmid. The data showed no difference in the overall end-joining activity between two types of cells; however, Brca1-deficient MEFs display a 50% reduction in precise end-joining activity (41).

The second approach used a retrovirus infection assay based on the observation that cells deficient in proteins involved in NHEJ show a reduced efficiency of retroviral infection (42,43). Their data revealed a 5–10-fold decrease of retroviral integration efficiency in Brca1-deficient cells compared with control cells. Third, they demonstrated that Brca1-/- MEFs exhibited a 50–100-fold deficiency in joining a defined chromosomal DSB introduced by a rare cutting endonuclease, I-SceI. These results provide evidence that BRCA1 promotes NHEJ mediated by microhomology (41). Consistently, the same group also provided an independent confirmation by showing that cell-free extracts from Brca1-null MEFs are deficient in NHEJ (44).

While the above experiments were carried out in Brca1 homozygous mutant mouse cells, human lymphoblasts heterozygous for a BRCA1 mutation (BRCA1+/-) exhibited decreased DNA repair activity (45,46). Using an in vivo host cell end-joining assay, Baldeyron et al. (46) observed a significant decrease in end-joining frequency in BRCA1-/- lymphoblastoid cells. Moreover, the fidelity of DNA end-joining was strongly reduced in all three BRCA1+/- cell lines in comparison to two control cell lines. They also showed that cell-free BRCA1+/- extracts were unable to promote accurate DNA end-joining in an in vitro reaction. Interestingly, the BRCA1 protein was about 20–30% the level of BRCA1 in wild type cells, which was significantly lower than the expected 50% (46). This finding provides a basis for the observed defect.

The finding that BRCA1 plays an essential role in NHEJ is significant, as this pathway repairs the majority of DSBs in mammalian cells (47). Together with the investigations showing that BRCA1 has an essential role in HRR, these studies provide a convincing explanation for why BRCA1-deficient cells are hypersensitive to {gamma}-irradiation, one of the most potent sources of DSBs. However, the involvement of BRCA1 in NHEJ is, on the surface, contradictory to a previous finding that mouse embryonic stem (ES) cells carrying a hypomorphic mutation of Brca1 exhibited increased non-homologous mediated recombination (18,48). Major differences in these systems are host cells (ES cells versus MEFs) and the nature of Brca1 mutations. The Brca1 mutant ES cells still express a short isoform, only missing exon 11 (26,48). It is conceivable that the presence of this isoform could support NHEJ. However, in conditional mice, which carry a Cre-loxP mediated deletion of Brca1 exons 5 and 6 (Brca1{Delta}5-6) in T-lymphocytes, Brca1 is not required for the in vivo NHEJ required for TCR V(D)J recombination (37). Because Brca1{Delta}5-6 disrupts all isoforms of Brca1 and is a candidate null mutation, it is possible that V(D)J represents one type of specific end joining that is not affected by the absence of BRCA1. Alternatively, intrinsic differences in host factors, such as T cells versus MEFs and whole animal versus cultured cells, may be culprits.

BRCA1 and NER
NER is divided into two pathways: global genomic repair (GGR), which removes lesions from the whole genome, and transcription-coupled repair (TCR), which preferentially removes lesions from the transcribed strand of expressed genes (3). Gowen et al. (49) reported that mouse ES cells deficient in Brca1 are defective in the ability to carry out TCR of oxidative DNA damage, and are hypersensitive to ionizing radiation and hydrogen peroxide. These results suggest that BRCA1 participates, directly or indirectly, in TCR of oxidative DNA damage. Consistently, expression of BRCA1 restores radiation resistance of a BRCA1-deficient human breast cancer cell line, HCC1397, through enhancement of TCR (50).

More recently, Hartman and Ford (51) studied the role of BRCA1 in two human U2OS osteosarcoma cell lines, UBR60 and E621. Cell line UBR60 carries wild-type p53 and cell line E621 is derived from UBR60, but is deficient for p53 due to stable expression of the human papillomavirus E6, which targets p53 for degradation. Both cell lines express low levels of endogenous BRCA1 and the exogenously transfected BRCA1 was controlled by tetracycline regulation (about a 4-fold induction of BRCA1 24 h after tetracycline removal). These cells were used as models to study the effects of BRCA1 and/or p53 on NER.

Their data showed that in the presence of tetracycline (low level of BRCA1), the efficiency of GGR is significantly lower in p53-deficient cells than p53 wild-type cells (3 versus 28% repair at 24 h). This observation is consistent with findings that loss of p53 function results in defective GGR (52,53). Notably, expression of BRCA1 restored GGR in p53-deficient E621 cells with 34% of DNA damages repaired at 24 h versus 3% without BRCA1 induction. Expression of BRCA1 in p53 wild-type UBR cells resulted in greater GGR than the same cells without BRCA1 induction (42 versus 28%) (51). These observations indicate that BRCA1 plays an important role in GGR.

Next, they investigated whether BRCA1 affects TCR of UV irradiation in these cells. Using strand-specific probes to an expressed gene (DHFR), they showed that BRCA1 mutation only affects repair on the untranscribed strand but not the transcribed strand upon UV irradiation. Thus, BRCA1 does not affect TCR induced by UV irradiation although it plays a role in TCR of oxidative DNA damage as shown previously (49).

Mechanisms of BRCA1 in DNA damage repair
Having reviewed evidence for the involvement of BRCA1 in a number of major DNA damage repair pathways, next we discuss possible mechanisms through which BRCA1 plays a role in these pathways.

BRCA1 interacts with proteins of DNA damage repair machinery.
A unique feature of BRCA1 is that it interacts directly or indirectly with many proteins that play important functions in multiple biological pathways (reviewed in 54). One of the first BRCA1 interacting proteins discovered was RAD51 (55,56), a homolog of yeast RecA, which functions in homologous recombination and DNA damage repair (57,58). BRCA1 co-localizes with RAD51 in intranuclear structures where DNA replication occurs after treatment with DNA damaging reagents (55). Consistently, it was demonstrated recently that Brca1 deficiency results in decreased Rad51 foci formation in cultured MEFs upon {gamma}-irradiation (59). BRCA1 and RAD51 are both specifically associated with developing synaptonemal complexes in meiotic cells. These findings suggest a functional interaction between BRCA1 and RAD51 in the meiotic and mitotic cell cycles, which, in turn, suggests a role for BRCA1 in the control of recombination and of genome integrity. Because RAD51 also interacts with BRCA2, it is proposed that BRCA1–BRCA2–RAD51 form a stable complex during DNA damage repair.

Another gene that is important in DSB repair, RAD50, also interacts with BRCA1 both in vitro and in vivo. Their data indicated that, upon ionizing irradiation, wild-type BRCA1 forms a complex with RAD50, MRE11 and p95/nibrin in discrete nuclear foci, which renders the treated cells less sensitive to methyl methanesulfonate. They further showed that formation of these irradiation-induced foci was dramatically reduced in BRCA1-deficient HCC/1937 breast cancer cells but was restored by transfection of wild-type BRCA1. This study suggests that BRCA1 is important for cellular responses to DNA damage mediated by the RAD50-MRE11-p95 complex (60).

A group of proteins associate with BRCA1 to form a large complex, called BASC (BRCA1-associated genome surveillance complex) (61). This complex includes tumor suppressors and DNA damage repair proteins, MSH2, MSH6, MLH1, ATM, BLM and the RAD50-MRE11-NBS1 protein complex. It also contains DNA replication factor C (RFC), a protein complex that facilitates the loading of PCNA onto DNA. As many members of this complex recognize abnormal DNA structures or damaged DNA, such as DSB, mismatched DNA, stalled replication forks, Holliday junctions and telomere repeats, this finding suggests that BRCA1 may function as a coordinator of multiple activities required for maintaining genome integrity. It was also shown that BRCA1 is co-localized with H2AX, a DNA damage sensor, on DNA damage sites (62). Consistently the failure of DNA damage repair caused by the absence of H2AX is associated with diminished Brca1 foci formation in H2AX-/- cells after irradiation (63).

BRCA1 transcriptionally regulates genes involved in DNA damage repair.
BRCA1 is a transcriptional factor, which regulates expression of many genes that are involved in multiple biological processes (reviewed in 54,64). So far, at least three genes that play a role in DNA damage repair have been found to be regulated by BRCA1. Overexpression of BRCA1 induces Gadd45 (a DNA damage repair and response gene), which plays an important role in NER (33,34,53). BRCA1 also transcriptionally regulates DDB2 (a gene defective in Xeroderma Pigmentasum group E cells and encoding the p48 damaged DNA binding protein) in the DNA repair response following UV-irradiation (51,65). Previous investigations have demonstrated that expression of these genes is p53 dependent and is required for efficient GGR, a subpathway of NER (66,67). Takimoto et al. (65) demonstrated that overexpression of BRCA1 restored expression of these genes in p53-deficient E621 cells to wild-type levels correlating with a restoration of CGR in these cells. Expression of BRCA1 also induced the expression of XPC (Xeroderma pigmentasum group C complimenting protein) in a wild-type p53-dependent manner, as the up-regulation of XPC by BRCA1 is most obvious in p53 wild-type UBR60 cells 48 h post BRCA1 induction, while the up-regulation is moderate in p53-deficient cells. These studies suggest a mechanism, by which BRCA1 functions as a transcriptional regulator of genes involved in NER at p53 dependent and independent ways.

Genetic instability in the absence of BRCA1
One of the direct consequences of the absence of genes responsible for DNA damage repair is genetic instability. To directly demonstrate this, Shen et al. (23) analyzed chromosomes isolated from E8.5–9.5 Brca1-deficient embryos generated by gene targeting. Using chromosome spectral karyotyping (SKY), which stains each chromosome with a distinct color (68), they showed that Brca1-deficient embryos displayed both numerical and structural chromosomal aberrations (23,69). Profound chromosome damages were also found in Brca1 mutant MEFs (69), mammary tumors (36,39), and lymphomas (70) that developed in Brca1 mutant mice.

Further analysis of mammary tumors derived from Brca1 conditional mice using comparative genome hybridization (CGH) and SKY demonstrated that Brca1-deficient tumors exhibit a pattern of chromosomal gains and losses similar to the pattern in human breast cancers (Fig. 1) (40). Most tumors (9/15) exhibited a gain of distal chromosome 11, a region that is orthologous to human chromosome 17q11-qter, the mapping position of ErbB2. Four of the tumors also exhibited a copy number loss of proximal chromosome 11 (11A–B), a region orthologous to human 17p. In eight of the 15 tumors, they observed whole or partial gain of chromosome 15 centering on 15D2–D3, orthologous to human chromosome 8q24, the map location of the c-Myc gene. Six tumors exhibited loss of all or a part of chromosome 14, including 14D3, the map location of Rb1. These observations are consistent with earlier studies that mammary tumors from Brca1 conditional mice exhibited increased expression of ErbB2, c-Myc and loss of p53 (38,39).



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  		Figure 1. Summary of CGH analysis of 15 Brca1 conditional mammary tumors. Eleven tumors that were derived from Brca1Ko/CoWap-Cre or Brca1Ko/CoMMTV-Cre mice are named as brt1-11. Four tumors were derived from Brca1Ko/CoWap-Crep53+/- mice and are referred to as pbrt1–4. Bars on the right side of the chromosome ideograms indicate gain and bars on the left side loss of genetic material. All gains and losses for a single tumor are represented in the same color. Bold lines denote high-level copy number increases. The chromosomal map position of the tumor suppressor genes p53 and Rb1 and the oncogenes ErbB2 and c-Myc is indicated.

 
Brca1 mutant cells also exhibited abnormal centrosome amplification and loss of G2-M cell cycle checkpoint control (69,71–73). These abnormalities are most likely independent of DNA damage and can also contribute to the observed genetic instability. Therefore the genetic instability observed in Brca1 mutant cells is likely a consequence of joint actions of these defects, i.e. absence of caretaker functions of Brca1, instead of just impaired DNA damage repair.


   SUMMARY AND FUTURE ASPECTS
TOP
 ABSTRACT
 INTRODUCTION
 SUMMARY AND FUTURE ASPECTS
REFERENCES
 
We have examined evidence that BRCA1 plays important roles in DNA damage repair, development and tumorigenesis. As summarized in Figure 2, the absence of BRCA1 impairs HRR, NHEJ and NER. The defect in DNA damage repair, combined with abnormalities in G2/M cell cycle checkpoint and centrosome duplication, could cause genetic instability in BRCA1-deficient cells. The accumulation of DNA damage, in turn, activates the p53 tumor suppressor gene and induces cell cycle arrest and apoptosis, which trigger a series of physiological responses, including defective cell proliferation, differentiation and transcription regulation. These abnormalities could have profound effects on development, leading to embryonic lethality observed in Brca1 mutants. On the other hand, the BRCA1 deficiency also increases the mutation rate of all the genes, including p53. The loss-of-function mutations of p53 will allow mutant cells containing DNA damage to survive and undergo clonal expansion and eventually result in tumorigenesis (Fig. 2).



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  		Figure 2. A schematic diagram demonstrating connections among genetic instability caused by BRCA1 deficiency, developmental abnormalities and tumorigenesis.

 
In human BRCA1 mutation carriers, tumorigenesis is mainly restricted to breast and ovary. The cancer specificity seems to be contributed by the interplay between BRCA1 and the estrogen signaling pathway, as BRCA1 has been known as a negative regulator of ER{alpha} signals (74–76). However, if the DNA damage repair functions of BRCA1 is universal, why are tumors only found in a subset of the tissues/organs? Because all the above analyses on DNA damage repair were carried out in cultured cell lines derived from a handful of tissues/organs, such as ES cells, MEF and lymphocytes, it will be interesting to know whether DNA damage repair functions of BRCA1 is also subject to tissue specificity. Does the observed discrepancy regarding a role of BRCA1 in NHEJ alert us on this issue? Future DNA damage repair studies should be performed using cells derived from more diverse tissues/organs, primarily from Brca1 mutant mice that carry hypomorphic mutations and survive to adulthood (22,29), as human BRCA1 homozygous mutation carriers do not normally survive (77). These Brca1 mutant mice, combined with a mutation reporter strain, such as BigBlue mice (78–80), could also be used as models to address spatial and temporal functions of Brca1 in DNA damage repair and genome stability in regard to tumorigenesis. So far, there is no report about a possible role of BRCA1 in base excision repair and MMR pathways. As BRCA1 interacts with proteins involved in these pathways (61), future experiments should also be directed to determine the functions of BRCA1 in these specific DNA damage repair pathways. These studies may uncover mechanisms underlying BRCA1 associated tumorigenesis in order to find effective ways to reduce DNA damage, stabilize the genome, and ultimately prevent breast cancer formation.


   ACKNOWLEDGEMENTS
 
We thank Drs Xavier Coumoul and Peggy Hsieh for critically reading and comments on the manuscript. We are grateful for Dr Thomas Ried for providing images that are used in Figure 1.


   FOOTNOTES
 
* To whom correspondence should be addressed. Tel: +1 3014027225; Fax: +1 3014801135; Email: chuxiad{at}bdg10.niddk.nih.gov Back


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