SV40 large T-antigen disturbs the formation of nuclear DNA-repair foci containing MRE11

Digweed, Martin; Demuth, Ilja; Rothe, Susanne; Scholz, Robert; Jordan, Andreas; Grötzinger, Carsten; Schindler, Detlev; Grompe, Markus; Sperling, Karl

doi:10.1038/sj.onc.1205616

Cited by 60 publications

(46 citation statements)

References 25 publications

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“…Perhaps the closest phenotype to that of hSNM1B knockdown cells occurs in cells derived from patients with FA, particularly in terms of their sensitivity to ICL-inducing agents in survival and chromosome stability. There are also several reports of increased radiosensitivity in FA cells (Carreau et al, 1999;Garcia-Higuera et al, 2001;Gatti, 2001;Digweed et al, 2002). Given this similarity, we considered the possibility that hSNM1B might function in the FA/ BRCA pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Cells derived from FA patients are characterized by chromosomal instability and hypersensitivity to ICL-inducing agents and, in at least some cases, to ionizing radiation (IR) (Carreau et al, 1999;Garcia-Higuera et al, 2001;Gatti, 2001;Digweed et al, 2002). The disease has a high degree of heterogeneity, with 11 known complementation groups (FA-A, B, C, D1, D2, E, F, G, I, J and K) (Levitus et al, 2003) and eight genes (FANCA, C, D1/BRCA2, D2, E, F, G, L) cloned thus far (Strathdee et al, 1992;Lo Len Foe et al, 1996; The Fanconi anaemia/breast cancer Consortium, 1996;de Winter et al, 1998de Winter et al, , 2000aTimmers et al, 2001;Howlett et al, 2002;Meetei et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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Human SNM1B is required for normal cellular response to both DNA interstrand crosslink-inducing agents and ionizing radiation

2004

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DNA interstrand crosslinks (ICLs) are critical lesions for the mammalian cell since they affect both DNA strands and block transcription and replication. The repair of ICLs in the mammalian cell involves components of different repair pathways such as nucleotide-excision repair and the double-strand break/homologous recombination repair pathways. However, the mechanistic details of mammalian ICL repair have not been fully delineated. We describe here the complete coding sequence and the genomic organization of hSNM1B, one of at least three human homologs of the Saccharomyces cerevisiae PSO2 gene. Depletion of hSNM1B by RNA interference rendered cells hypersensitive to ICL-inducing agents. This requirement for hSNM1B in the cellular response to ICL has been hypothesized before but never experimentally verified. In addition, siRNA knockdown of hSNM1B rendered cells sensitive to ionizing radiation, suggesting the possibility of hSNM1B involvement in homologous recombination repair of double-strand breaks arising as intermediates of ICL repair. Monoubiquitination of FANCD2, a key step in the FANC/BRCA pathway, is not affected in hSNM1B-depleted HeLa cells, indicating that hSNM1B is probably not a part of the Fanconi anemia core complex. Nonetheless, similarities in the phenotype of hSNM1B-depleted cells and cultured cells from patients suffering from Fanconi anemia make hSNM1B a candidate for one of the as yet unidentified Fanconi anemia genes not involved in monoubiquitination of FANCD2.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human SNM1B is required for normal cellular response to both DNA interstrand crosslink-inducing agents and ionizing radiation

2004

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“…Furthermore, SV40 large T antigen can disrupt the focus formation of Mre11 in both T-antigen immortalized cells and in cells transiently tranfected with T-antigen. 22 Therefore, it is also possible that SV40 T-antigen and the abnormal DNA damage response pathway in our 293T system contribute to the appearance of the nonspecific RCA signal. It should be straightforward to bypass these problems in future work by producing cell lines that are stably transfected with the HO cleavage site, and harbor an HO endonuclease gene under the control of an inducible promoter.…”

Section: Discussionmentioning

confidence: 99%

“…Both results suggest that infection with these DNA viruses induces a DNA damage response, as has also been observed for other DNA viruses. 22,23 Adenovirus has a linear double-stranded DNA genome. It is possible that infected cells sense large amounts of exogenous viral DNA as DSBs, thus activating the response pathway, including the phosphorylation of histone H2AX.…”

Section: Discussionmentioning

confidence: 99%

In situ Detection of Specific DNA Double Strand Breaks using Rolling Circle Amplification

Li¹,

Young²,

Lizardi³

et al. 2005

Cell Cycle

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Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/abstract.php?id=2211 KEY WORDSDNA Methodological ReportIn Situ Detection of Specific DNA Double Strand Breaks Using Rolling Circle Amplification ABSTRACTWe have developed a method to localize DNA double strand breaks (DSBs) in situ in cultured mammalian cells. Adenoviruses encoding Saccharomyces cerevisiae HO endonuclease and its cleavage site were used to induce site-specific DSBs. Rolling circle amplification (RCA), a sensitive method that allows the detection of single molecular event by rapid isothermal amplification, was used to localize the broken ends in situ. Punctate RCA signals were only seen in the cells that had been infected with both adenoviruses encoding HO endonuclease and HO cleavage site, but not in the cells mock-infected or infected with the site or endonuclease virus only. With use of a chemical crosslinker, in situ RCA and immunofluorescence (IF) can be performed simultaneously on the same sample. This methodology provides a novel approach for investigation of DNA recombination, DNA repair, and checkpoint controls in mammalian cells.

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“…Some of the corresponding gene products are required for the relocalization of recombination factors into DNA repair foci, which is an essential process during HR (Digweed et al, 2002). Importantly, many of these tumor suppressor proteins have been purified as part of a large protein complex known as BASC (BRCA1-associated genome surveillance complex), which may represent an assembly of DSB repair surveillance factors (Wang et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Differences in the association of p53 phosphorylated on serine 15 and key enzymes of homologous recombination

Restle¹,

Janz²,

Wiesmüller³

2005

Oncogene

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Phosphorylation of p53 on serine 15 by ATM or ATR is a frequent modification and initiates a cascade of posttranslational modifications. To identify possible mechanisms that modulate p53 functions in recombination surveillance, we compared the nuclear localization of p53 phosphorylated on serine 15 (p53pSer15) and the key enzymes of homologous recombination (HR) after replication fork stalling. We demonstrate an almost mutually exclusive subcompartmentalization with Rad52, while p53pSer15 was colocalizing with 40-60% of the Rad51 and Mre11 foci. Therefore, possible sites of p53pSer15-dependent regulation seem to be sites of Rad51-rather than Rad52-dependent HR processes. Remarkably, the association of p53pSer15 with repair complexes containing Rad51 or Mre11 was transient, because less than 20% of the Rad51 and Mre11 foci overlapped with p53pSer15 after 6 h. When we examined colocalization and coimmunoprecipitation of p53pSer15 and the RecQ helicase BLM with recombination surveillance and proapoptotic functions, we observed colocalization within a fraction of approximately 70% of the BLM foci and stable physical interactions until 6 h after replication arrest. Our data suggest that p53pSer15 plays a dual role in the functional interactions with early complexes of Rad51-dependent recombination and with BLM-associated surveillance and signalling complexes within distinct nuclear subcompartments.

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SV40 large T-antigen disturbs the formation of nuclear DNA-repair foci containing MRE11

Cited by 60 publications

References 25 publications

Human SNM1B is required for normal cellular response to both DNA interstrand crosslink-inducing agents and ionizing radiation

Human SNM1B is required for normal cellular response to both DNA interstrand crosslink-inducing agents and ionizing radiation

In situ Detection of Specific DNA Double Strand Breaks using Rolling Circle Amplification

Differences in the association of p53 phosphorylated on serine 15 and key enzymes of homologous recombination

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