The DDB2 nucleotide excision repair gene product p48 enhances global genomic repair in p53 deficient human fibroblasts

Fitch, Maureen E.; Cross, Irina V.; Turner, Stephanie; Adimoolam, Shanthi; Lin, Cindy; Williams, K.; Ford, James M.

doi:10.1016/s1568-7864(03)00066-1

Cited by 89 publications

(64 citation statements)

References 23 publications

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“…However, DDB1 was not needed for the removal of another major photolesion, 6-4PP, which is rapidly eliminated from DNA of living organisms. This differential lesion-specific role of DDB1 in NER is functionally similar to that of DDB2 (12,30,39). This is not surprising as the underlying mechanism to initiate productive repair is based on the binding of the heterodimeric protein to DNA damage.…”

Section: Discussionmentioning

confidence: 73%

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DNA Damage Binding Protein Component DDB1 Participates in Nucleotide Excision Repair through DDB2 DNA-binding and Cullin 4A Ubiquitin Ligase Activity

Wang²,

Zhu³

et al. 2006

Cancer Research

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Functional defect in DNA damage binding (DDB) activity has a direct relationship to decreased nucleotide excision repair (NER) and increased susceptibility to cancer. DDB forms a complex with cullin 4A (Cul4A), which is now known to ubiquitylate DDB2, XPC, and histone H2A. However, the exact role of DDB1 in NER is unclear. In this study, we show that DDB1 knockdown in human cells impaired their ability to efficiently repair UV-induced cyclobutane pyrimidine dimers (CPD) but not 6-4 photoproducts (6-4PP). Extensive nuclear protein fractionation and chromatin association analysis revealed that upon irradiation, DDB1 protein is translocated from a loosely bound to a tightly bound in vivo chromatin fraction and the DDB1 translocation required the participation of functional DDB2 protein. DDB1 knockdown also affected the translocation of Cul4A component to the tightly bound form in UV-damaged chromatin in vivo as well as its recruitment to the locally damaged nuclear foci in situ. However, DDB1 knockdown had no effect on DNA damage binding capacity of DDB2. The data indicated that DDB2 can bind to damaged DNA in vivo as a monomer, whereas Cul4A recruitment to damage sites depends on the fully assembled complex. Our data also showed that DDB1 is required for the UV-induced DDB2 ubiquitylation and degradation. In summary, the results suggest that (a) DDB1 is critical for efficient NER of CPD; (b) DDB1 acts in bridging DDB2 and ubiquitin ligase Cul4A; and (c) DDB1 aids in recruiting the ubiquitin ligase activity to the damaged sites for successful commencement of lesion processing by NER. (Cancer Res 2006; 66(17): 8590-7)

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Section: Discussionmentioning

confidence: 73%

“…Several studies have shown that restoration of DDB2 in DDB2-deficient cells enhanced the efficiency of CPD removal (14,30,39). In addition, our recent work has shown that Cul4A is required for global genomic repair of CPD but not of 6-4PP (40).…”

Section: Discussionmentioning

confidence: 80%

DNA Damage Binding Protein Component DDB1 Participates in Nucleotide Excision Repair through DDB2 DNA-binding and Cullin 4A Ubiquitin Ligase Activity

Wang²,

Zhu³

et al. 2006

Cancer Research

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“…Several mechanisms have been suggested for the observed enhancement of DNA repair by p53. These include transcriptional upregulation of DNA repair factors such as DDB2 and XPC (Adimoolam and Ford, 2002;Amundson et al, 2002;Tan and Chu, 2002;Fitch et al, 2003), recruitment of repair factors to sites of DNA damage through physical interaction with p53 (Wang et al, 2003) and the ability of p53 to function as a chromatin accessibility factor to allow access of repair factors to sites of damage (Rubbi and Milner, 2003). Given that E2F1 can upregulate the expression of a number of DNA repair genes (Wang et al, 1999;Polager et al, 2002;Ren et al, 2002) and that E2F1 physically associates with several DNA repair factors (Hayes et al, 1998;Maser et al, 2001;Liu et al, 2003), it is quite possible that like p53, the antiapoptotic effect of E2F1 is related to a stimulation of DNA repair.…”

Section: E2f1 Regulation Of Apoptosismentioning

confidence: 99%

Regulation of epidermal apoptosis and DNA repair by E2F1 in response to ultraviolet B radiation

et al. 2005

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The E2F1 transcription factor regulates the expression of genes involved in cell proliferation, apoptosis and DNA repair. Following DNA damage, E2F1 is phosphorylated and stabilized, but the physiological role of E2F1 in the response to DNA damage is unclear. We find that mice lacking E2F1 have increased levels of epidermal apoptosis compared to wild-type mice following exposure to ultraviolet B (UVB) radiation. Moreover, transgenic overexpression of E2F1 in basal layer keratinocytes suppresses apoptosis induced by UVB. Inhibition of UVB-induced apoptosis by E2F1 is unexpected given that most studies have demonstrated a proapoptotic function for E2F1. E2F1-mediated suppression of apoptosis does not involve alterations in mitogen-activated protein kinase activation or Bcl-2 downregulation in response to UVB and is independent of p53. Instead, inhibition of UVBinduced apoptosis by E2F1 correlates with a stimulation of DNA repair. Mice lacking E2F1 are impaired for the removal of DNA photoproducts, while E2F1 transgenic mice repair UVB-induced DNA damage at an accelerated rate compared to wild-type mice. These findings suggest that E2F1 participates in the response to UVB by promoting DNA repair and suppressing apoptosis.

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“…DDB2 binds with high affinity to photoproducts, induces a bending of the DNA to approximately 40° and facilitates the flipping of the affected bases that are recognized and bound by the XPC/hHR23B complex, which further introduces structural changes into the DNA (Min and Pavletich, 2007;Scrima et al, 2008). DDB2 is part of a DDB1-CUL4-RBX1 (DCX) E3 ligase that mediates the polyubiquitination of histones, XPC and DDB2 itself (Rapic-Otrin et al, 2002;Fitch et al, 2003;Sugasawa et al, 2005;Chen et al, 2006;Kapetanaki et al, 2006;Wang et al, 2006). As a consequence, DDB2 is degraded via the 26S proteasome clearing the way for later repair stages (Rapic-Otrin et al, 2002;Fitch et al, 2003;Chen et al, 2006).…”

Section: Nucleotide Excision Repairmentioning

confidence: 99%

“…DDB2 is part of a DDB1-CUL4-RBX1 (DCX) E3 ligase that mediates the polyubiquitination of histones, XPC and DDB2 itself (Rapic-Otrin et al, 2002;Fitch et al, 2003;Sugasawa et al, 2005;Chen et al, 2006;Kapetanaki et al, 2006;Wang et al, 2006). As a consequence, DDB2 is degraded via the 26S proteasome clearing the way for later repair stages (Rapic-Otrin et al, 2002;Fitch et al, 2003;Chen et al, 2006). Interestingly ubiquitination has the opposite effect on XPC leading to its stabilization and activation (Sugasawa et al, 2005).…”

Section: Nucleotide Excision Repairmentioning

confidence: 99%

Recognition and Repair Pathways of Damaged DNA in Higher Plants

Biedermann¹,

Mooney²,

Hellmann³

2011

Selected Topics in DNA Repair

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The DDB2 nucleotide excision repair gene product p48 enhances global genomic repair in p53 deficient human fibroblasts

Cited by 89 publications

References 23 publications

DNA Damage Binding Protein Component DDB1 Participates in Nucleotide Excision Repair through DDB2 DNA-binding and Cullin 4A Ubiquitin Ligase Activity

DNA Damage Binding Protein Component DDB1 Participates in Nucleotide Excision Repair through DDB2 DNA-binding and Cullin 4A Ubiquitin Ligase Activity

Regulation of epidermal apoptosis and DNA repair by E2F1 in response to ultraviolet B radiation

Recognition and Repair Pathways of Damaged DNA in Higher Plants

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