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Bloom syndrome


Wednesday 19 November 2003

Bloom syndrome is an autosomal recessive disorder characterized by proportionate pre- and postnatal growth deficiency, sun-sensitive telangiectatic hypo- and hyperpigmented skin, predisposition to malignancy and chromosomal instability.

The syndrome initially described by Bloom in 1954 is characterized by pre- and postnatal growth deficiency, sunlight sensitivity, hypo- and hyper-pigmented skin, predisposition to malignancy and chromosomal instability. Light-induced telangiectasia develops typical "butterfly" lesions on the patient’s face.


- mutations in the gene encoding DNA helicase RecQ protein-like-3 (RECQL3) (15q26.1) (MIM.604610)


- Cells from patients with BS grow slowly in culture, with low plating efficiencies and long generation times.

- DNA synthesis is unpaired, with an accumulation of replication intermediates (Giannelli et al., 1977), suggesting a defect associated with DNA replication, although this is not yet understood.

- The genetic mapping of BS related families allowed the cloning of the gene responsible for this disease, denominated BLM or RECQL3 (Ellis et al., 1995). Strikingly, this gene has homology with a family of RecQ helicases, named after the Escherichia coli RecQ gene.

- In bacteria this gene is a member of the RecF recombination pathway, involved in conjugational recombination proficiency and UV resistance. Ellis et al. (1995) suggested that the absence of the BLM gene product probably destabilizes other enzymes that participate in DNA replication and repair, perhaps through direct interactions and through more general responses to DNA damage.

- More recently, a second human gene member of the RecQ family was identified, WRN, and defects on this gene may lead to the Werner syndrome (WS) (Yu et al., 1996).

- Although DNA repair seems to be normal in the cells from BS and WS, the BLM and WRN proteins are implicated in the DNA metabolism. They probably participate in a large family of RecQ helicases in the human genome, important to maintain genomic stability.

- The RECQL3 gene is mutated in BS, a rare disorder associated with pleiotropic phenotypes including immunodeficiency, impaired fertility, proportional dwarfism, sun-induced facial erythema and a predisposition to cancer (mean age at cancer diagnosis of approximately 24 years).

This disorder is of particular interest because affected individuals are susceptible to the full range of cancers seen in the normal population. BS cells show a high frequency of genetic recombination events, particularly sister chromatid exchanges (SCEs) and an elevated rate of somatic mutation.

BRCA1 is the protein defective in some cases of hereditary breast cancer susceptibility. The recent identification of RECQL3 as part of the BRCA1-associated genome surveillance complex (BASC), links RECQL3 with a number of tumour suppressor and DNA damage repair proteins.

The BASC complex includes MSH2, MHS6, MLH1, ATM, RECQL3, the RAD50-MRE11-NBS1 complex and DNA replication factor C. Many components of this complex have roles in recognition of DNA damage/unusual DNA structures, suggestive of this complex performing some kind of ’sensor’ role.

To examine the role of BLM within BASC, the subcellular localization of RECQL3 and BRCA1 was analysed before and after exposure to DNA damaging agents.

In untreated cells, RECQL3 and BRCA1 colocalization was limited to a few bright nuclear foci. However, after treatment with hydroxyurea or ionizing radiation, colocalization was greatly enhanced in those cells that were in mid-to-late S phase or in G2. This could be indicative of specific requirement for BLM/BRCA1 in replication/repair of late replicating DNA.

Consistent with a role for BLM (possibly within BASC) in recognizing abnormal DNA structures, we have shown recently that BLM is able to unwind a variety of unusual DNA structures, including G-quadruplex, synthetic X-junctions (models for the Holliday junction), bubbles and forked DNA (P. Mohaghegh et al., submitted for publication).

RECQL3 binds to the 70 kDa subunit of the heterotrimeric, single-stranded DNA binding protein, replication protein A (RPAs). This interaction stimulates the helicase activity of RECQL3.

RPAs are involved in DNA replication, repair and recombination, and can be detected on meiotic prophase chromosomes where it appears to play a role in both homologous synapsis and recombination.

RECQL3 and RPAs also colocalise in meiotic prophase nuclei of mouse spermatocytes. Potentially, RECQL3 and RPAs could work together to unwind various DNA structures to facilitate DNA recombination during meiosis, perhaps through resolving recombination intermediates.

A role for RECQL3 in recombinational repair has been proposed recently by our group, as a result of the finding of a direct interaction between RECQL3 and the RAD51 recombinase enzyme.

RAD51 is the eukaryotic homologue of the E.coli RecA protein, which is vital for homologous recombination and recombinational repair of DNA double-strand breaks.

RECQL3 and RAD51 were found to interact directly in vitro and to co-immunoprecipitate from nuclear extracts.

As discussed above, RECQL3 localizes to nuclear foci in response to DNA damage and colocalizes with BRCA1.

RECQL3 also colocalizes with a subset of RAD51 nuclear foci, which have been suggested to be sites of ongoing DNA repair. As with the RECQL3 /BRCA1 colocalization, the number of colocalising RECQL3 /RAD51 foci increases after treatment of cells with ionizing radiation. The precise functional role for the RECQL3 /RAD51 interaction is not currently known.

RECQL3 preferentially binds to and melts DNA D-loops that can be formed by RAD51. D-loop structures model the initial intermediate formed during homologous recombination, and RECQL3 and RAD51 may have antagonistic roles in dealing with DNA structures arising at collapsed replication forks.

A second possibility is that the RECQL3 -RAD51 complex exists to coordinate different steps of homologous recombination. In this context, we have shown recently that RECQL3 binds to the Holliday junction recombination intermediate and promotes ATP-dependent branch migration of these junctions.

Some, but not all, of the nuclear foci that include BASC, RECQL3 and RAD51 colocalize with promyelocytic leukemia (PML) nuclear bodies.

It was shown in three independent reports that RECQL3 localises to PML bodies in the nucleoplasm of normal cells. One report suggested, however, that BLM localizes to the nucleolus during S phase.

In contrast, we have shown that BLM can be found in replication foci during S phase. It has been shown that BS cell lines bud out micronuclei during S phase, and micronuclei are proposed to be part of a p53-dependent process in response to the stalling of DNA replication forks.

Interestingly, in PML-/- cell lines, RECQL3 fails to accumulate in nuclear foci, and in these cell lines the level of SCEs is higher than in PML+/+ controls. These results suggest that PML is required for the localization of RECQL3 to nuclear foci, pointing to PML being a regulator of RECQL3 , and to a role for the PML body in regulating genome stability.

The ability of PML to regulate RECQL3 and other PML interacting proteins is potentially controlled by SUMO-1 modification of PML and other proteins, including possibly BLM.

The first direct biochemical evidence for a role for RECQL3 in DNA replication was provided by studies with the RECQL3 homologue in Xenopus (xRECQL3).

Antibodies were raised against xBLM and used in a series of immunodepletion experiments. DNA replication was strongly inhibited (5- to 10-fold) in Xenopus egg extracts depleted of xBLM. This inhibition was rescued by the addition of recombinant xBLM.

These results, showing a critical role for xBLM in DNA replication are apparently in contradiction to previous observations showing that yeast sgs1 and rqh1 mutants, as well as human BS cells lacking RECQL3, are viable and can perform near normal DNA replication.


- Franchitto A, Pichierri P. Protecting genomic integrity during DNA replication: correlation between Werner’s and Bloom’s syndrome gene products and the MRE11 complex. Hum Mol Genet. 2002 Oct 1;11(20):2447-53. PMID: 12351580

- Karow, J.K., Chakraverty, R.K. and Hickson, I.D. The Bloom’s syndrome gene product is a 3’5’ DNA helicase. J. Biol. Chem. 272: 30611-30614, 1997

- Ellis NA, German J. Molecular genetics of Bloom’s syndrome. Hum Mol Genet. 1996;5 Spec No:1457-63. PMID: 8875252

- Bloom, D. (1954). Congenital telangiectatic erythema resembling lupus erythematosus in dwarfs. Am. J. Dis. Child. 88: 754-758.