Ultraviolet light sensitivity and delayed DNA-chain maturation in Bloom's syndrome fibroblasts

Giannelli, F.; Benson, P. F.; Pawsey, S.A.; Polani, P. E.

doi:10.1038/265466a0

Cited by 151 publications

(37 citation statements)

References 9 publications

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“…This indicates that BLM is likely to act during the S phase, possibly at the level of DNA replication, as already suggested by the observation that BS cells exhibit replication abnormalities, which include a retarded replication-fork elongation (Hand and German, 1975;Gianneli et al, 1977) and abnormal replication intermediates (Lonn et al, 1990). It is also interesting that BLM carries the L2G box consensus which has been detected in a number of proteins involved in regulation of DNA replication, initiation and/or progression (KuÈ hne and Banks, 1998).…”

Section: Discussionsupporting

confidence: 57%

“…Cells derived from BS patients exhibit a complex phenotype associating in particular replication abnormalities (Hand and German, 1975;Gianneli et al, 1977;Lonn et al, 1990), high rate of mutations and recombination, and chromosomal breaks (for review, German, 1993). Even though the BLM gene and several mutations responsible for Bloom's syndrome have been identi®ed in the last 4 years, the physiological function of the gene product remains uncharacterized.…”

Section: Discussionmentioning

confidence: 99%

“…In parallel, because BLM defect is known to result in abnormalities associated with replication (Hand and German, 1975;Gianneli et al, 1977;Lonn et al, 1990), we treated HeLa cells with two DNA replication inhibitors which both block chain elongation (Levenson and Hamlin, 1993): hydroxyurea which inhibits ribonucleotide reductase (Skoog and NordenskjoÈ ld, 1971) and aphidicolin which interacts with DNA polymerases (Wang, 1991). G1, S and G2/M sorted HeLa cells were compared to untreated, aphidicolin or hydroxyurea treated HeLa cells for expression of BLM as detected by Western blot analysis using the 1340 antibody.…”

Section: Introductionmentioning

confidence: 99%

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Cell cycle regulation of the endogenous wild type Bloom's syndrome DNA helicase

et al. 2000

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Bloom's syndrome (BS) is a rare human autosomal recessive disorder characterized by an increased risk to develop cancer of all types. BS cells are characterized by a generalized genetic instability including a high level of sister chromatid exchanges. BS arises through mutations in both alleles of the BLM gene which encodes a 3' ± 5' DNA helicase identi®ed as a member of the RecQ family. We developed polyclonal antibodies speci®c for the NH 2 -and COOH-terminal region of BLM. Using these antibodies, we analysed BLM expression during the cell cycle and showed that the BLM protein accumulates to high levels in S phase, persists in G2/ M and sharply declines in G1, strongly suggestive of degradation during mitosis. The BLM protein is subject to post-translational modi®cations in mitosis, as revealed by slow migrating forms of BLM found in both demecolcine-treated cells and in mitotic cells isolated from non-treated asynchronous populations. Phosphatase treatment indicated that phosphorylation events were solely responsible for the appearance of the retarded moieties, a possible signal for subsequent degradation. Together, these results are consistent with a role of BLM in a replicative (S phase) and/or post-replicative (G2 phase) process.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cell cycle regulation of the endogenous wild type Bloom's syndrome DNA helicase

et al. 2000

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“…BLM de®ciency is known to result in abnormalities associated with replication (Hand and German, 1977;Gianneli et al, 1977;Lonn et al, 1990), and several lines of evidences suggest that a BLM defect would result in an accumulation of Holliday junctions that would be mainly resolved by sister chromatid exchanges (Karow et al, 2000a;Wang et al, 2000a). Furthermore, we previously showed that BLM accumulates in cells treated with the DNA replication inhibitors hydroxyurea and aphidicolin, and reaches the levels detected in S phase cells, indicating that BLM is involved in the S phase of the cell cycle .…”

Section: Resultsmentioning

confidence: 99%

Bloom's syndrome protein response to ultraviolet-C radiation and hydroxyurea-mediated DNA synthesis inhibition

et al. 2002

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Bloom's syndrome (BS) arises through mutations in both copies of the BLM gene that encodes a RecQ 3'-5' DNA helicase. BS patients are predisposed to developing all the cancers that aect the general population, and BS cells exhibit marked genetic instability. We showed recently that BLM protein contributes to the cellular response to ionizing radiation by acting as downstream ATM kinase eector. We now show that following UVC treatment, BLM-de®cient cells exhibit a reduction in the number of replicative cells, a partial escape from the G2/ M cell cycle checkpoint, and have an altered p21 response. Surprisingly, we found that hydroxyureatreated BLM-de®cient cells exhibit an intact S phase arrest, proper recovery from the S phase arrest, and intact p53 and p21 responses. We also show that the level of BLM falls sharply in response to UVC radiation. This UVC-induced reduction in BLM does not require a functional ATM gene and does not result from a subcellular compartment change. Finally, we demonstrate that exposure to UVC and hydroxyurea treatment both induce BLM phosphorylation via an ATM-independent pathway. These results are discussed in the light of their potential physiological signi®cance with regard to the role of BLM in the cellular pathways activated by UVC radiation or HU-mediated inhibition of DNA synthesis.

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“…Interestingly, the Bloom's helicase was recently reported to co-immunoprecipitate with BRCA1 . In view of the defects in daughter strand synthesis in Bloom's cells, it is tempting to consider the primary defect as one of DNA polymerase/replication fork processivity (Gianneli et al, 1977;Hand and German, 1977). However, the fact that yeast strains mutated for Bloom's homologs exhibit sensitivity to HU points to a defect in processes subsequent to replication arrest, not only to an increased rate of DNA polymerase stalling (Stewart et al, 1997;Yamagata et al, 1998).…”

Section: Dna Polymerase Stalling and Recombination In Eukaryotesmentioning

confidence: 99%

DNA polymerase stalling, sister chromatid recombination and the BRCA genes

2000

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Heritable predisposition to breast and/or ovarian cancer is determined, in part, by germline mutation a ecting one of two tumor suppressor genes, BRCA1 and BRCA2 (Miki et al., 1994;Wooster et al., 1995). These genes are required for the maintenance of genomic integrity and for control of homologous recombination in somatic and meiotic cells. Here, we explore the hypothesis that a major role of the BRCA gene products in the somatic DNA damage response centers upon the control of recombination between sister chromatids during S phase. By analogy with model organisms, we suggest that stalling of a mammalian DNA polymerase complex by its encounter with abnormal DNA structure calls forth a series of responses that collaborate to enforce appropriate recombinational outcomes, and to suppress inappropriate or`illegitimate' recombination. Oncogene (2000) 19, 6176 ± 6183.

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Ultraviolet light sensitivity and delayed DNA-chain maturation in Bloom's syndrome fibroblasts

Cited by 151 publications

References 9 publications

Cell cycle regulation of the endogenous wild type Bloom's syndrome DNA helicase

Cell cycle regulation of the endogenous wild type Bloom's syndrome DNA helicase

Bloom's syndrome protein response to ultraviolet-C radiation and hydroxyurea-mediated DNA synthesis inhibition

DNA polymerase stalling, sister chromatid recombination and the BRCA genes

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