Altered temporal expression of DNA repair in hypermutable Bloom's syndrome cells.

Gupta, Pawan; Sirover, Michael A.

doi:10.1073/pnas.81.3.757

Cited by 33 publications

(11 citation statements)

References 32 publications

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“…Elevated levels of oxidative DNA lesions have been detected in BS, WS and RTS patient cells [51–53], and human WRN, BLM, RECQL4 and RecQ5β have been shown to interact with and modulate activities of several proteins involved in BER [53, 73–75]. When exposed to oxidative damage by H 2 O 2 , WS cells fail to activate PARP-1 and bypass cell proliferation arrest [41].…”

Section: Discussionmentioning

confidence: 99%

RECQ1 plays a distinct role in cellular response to oxidative DNA damage

et al. 2012

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RECQ1 is the most abundant RecQ homolog in humans but its functions have remained mostly elusive. Biochemically, RECQ1 displays distinct substrate specificities from WRN and BLM, indicating that these RecQ helicases likely perform non-overlapping functions. Our earlier work demonstrated that RECQ1-deficient cells display spontaneous genomic instability. We have obtained key evidence suggesting a unique role of RECQ1 in repair of oxidative DNA damage. We show that similar to WRN, RECQ1 associates with PARP-1 in nuclear extracts and exhibits direct protein interaction in vitro. Deficiency in WRN or BLM helicases have been shown to result in reduced homologous recombination and hyperactivation of PARP under basal condition. However, RECQ1-deficiency did not lead to PARP activation in undamaged cells and nor did it result in reduction in homologous recombination repair. In stark contrast to what is seen in WRN-deficiency, RECQ1-deficient cells hyperactivate PARP in a specific response to H2O2 treatment. RECQ1-deficient cells are more sensitive to oxidative DNA damage and exposure to oxidative stress results in a rapid and reversible recruitment of RECQ1 to chromatin. Chromatin localization of RECQ1 precedes WRN helicase, which has been shown to function in oxidative DNA damage repair. However, oxidative DNA damage-induced chromatin recruitment of these RecQ helicases is independent of PARP activity. As other RecQ helicases are known to interact with PARP-1, this study provides a paradigm to delineate specialized and redundant functions of RecQ homologs in repair of oxidative DNA damage.

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Section: Discussionmentioning

confidence: 99%

RECQ1 plays a distinct role in cellular response to oxidative DNA damage

et al. 2012

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“…The existence of a heat-resistant factor that is associated with DNA ligases and promotes ligase activity on linear DNA has been observed in human fibroblasts as well as Xenopus laevis ovaries (30,31). In addition, it has been proposed that the ligation of nonhomologous DNA ends is facilitated by proteins that align the ends (32) (26,33), and an incomplete cDNA encoding the 3' half of DNA ligase I is sufficient for complementation of cdc9 (23 (11)(12)(13)(14) have identified an alteration in the structure and expression of uracil DNA glycosylase and hypoxanthine DNA glycosylase in BS cells. These enzymes are unlikely to affect the levels of DNA ligase I activity directly.…”

Section: Discussionmentioning

confidence: 99%

“…In BS cells this induction is delayed, and maximal levels ofuracil and hypoxanthine DNA glycosylases are not attained until late in S phase, although the maximal activity of these enzymes is not reduced in BS cells. In addition, a monoclonal antibody that recognizes uracil DNA glycosylase from normal cells is unreactive with BS uracil DNA glycosylase, indicating that the enzyme is structurally altered or modified in BS cells (11)(12)(13)(14).…”

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confidence: 99%

A wild-type DNA ligase I gene is expressed in Bloom's syndrome cells.

Petrini

Huwiler

Weaver

1991

Proc. Natl. Acad. Sci. U.S.A.

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Alteration of DNA ligase I activity is a consistent biochemical feature of Bloom's syndrome (BS) cells.DNA ligase I activity in BS cells either is reduced and abnormally thermolabile or is present in an anamolously dimeric form. To assess the role of DNA ligase function in the etiology of BS, we have cloned the DNA ligase I cDNA from normal human cells by a PCR strategy using degenerate oligonucleotide primers based on conserved regions of the Saccharomyces cerevisiae and Schizosaccharomyces pombe DNA ligase genes.Human DNA ligase I cDNAs from normal and BS cells complemented a S. cerevisiae DNA ligase mutation, and protein extracts prepared from S. cerevisiae transformants expressing normal and BS cDNA contained comparable levels of DNA ligase I activity. DNA sequencing and Northern blot analysis of DNA ligase I expression in two BS human fibroblast lines representing each of the two aberrant DNA ligase I molecular phenotypes demonstrated that this gene was unchanged in BS cells. Thus, another factor may be responsible for the observed reduction in DNA ligase I activity associated with this chromosomal breakage syndrome.To assess the molecular basis of this disease, we have cloned the cDNA corresponding to the human DNA ligase I gene expressed in normal cells and from two BS fibroblast lines, GM8505 and GM5289. The DNA ligase I gene was isolated by a PCR strategy employing degenerate oligonucleotides based on conserved regions of the DNA ligase genes of Saccharomyces cerevisiae and Schizosaccharomyces pombe (15). A complete DNA sequence analysis from two BS cell lines revealed that each BS DNA ligase I gene was indistinguishable from the wild-type gene. A single 3.1-kilobase (kb) DNA ligase I mRNA was detected at normal steady-state levels in BS cells by Northern blot analysis. Also, the GM8505 DNA ligase I gene was able to complement the S. cerevisiae cdc9 DNA ligase mutation. Given the reduction in DNA ligase I activity in BS cells, these results suggest that a factor which modulates DNA ligase I activity in normal cells is defective in BS. Alternatively, a defect in a modifying activity that acts upon DNA ligase I and some DNA-repair enzymes may account for the altered repair phenotypes in BS cells.

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“…BS cells are also hypermutable (61,164,169). Reports on BS cell sensitivity to DNA damage are variable and may reflect cell cycle effects (60,72). A delay in DNA chain maturation has been noted (58).…”

Section: Bloom Syndromementioning

confidence: 99%

DNA Damage Processing Defects and Disease

Moses

2001

Annu. Rev. Genom. Hum. Genet.

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Inherited defects in DNA repair or the processing of DNA damage can lead to disease. Both autosomal recessive and autosomal dominant modes of inheritance are represented. The diseases as a group are characterized by genomic instability, with eventual appearance of cancer. The inherited defects frequently have a specific DNA damage sensitivity, with cells from affected individuals showing normal resistance to other genotoxic agents. The known defects are subtle alterations in transcription, replication, or recombination, with alternate pathways of processing permitting cellular viability. Distinct diseases may arise from different mutations in one gene; thus, clinical phenotypes may reflect the loss of different partial functions of a gene. The findings indicate that partial defects in transcription or recombination lead to genomic instability, cancer, and characteristic disease phenotypes.

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Altered temporal expression of DNA repair in hypermutable Bloom's syndrome cells.

Cited by 33 publications

References 32 publications

RECQ1 plays a distinct role in cellular response to oxidative DNA damage

RECQ1 plays a distinct role in cellular response to oxidative DNA damage

A wild-type DNA ligase I gene is expressed in Bloom's syndrome cells.

DNA Damage Processing Defects and Disease

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