Independent roles of XRCC1’s two BRCT motifs in recovery from methylation damage

Kubota, Yukiho; Horiuchi, Saburo

doi:10.1016/s1568-7864(02)00242-2

Cited by 38 publications

(41 citation statements)

References 25 publications

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“…Alternatively, because the interaction of XRCC1 with Lig3, this complex could be preformed and as such participate in all the pathway. Mutations in the different domains of XRCC1 yield distinct cellular phenotypes (41)(42)(43), supporting the idea that they interfere with the association to specific partners, therefore affecting specific repair pathways.…”

Section: Xrcc1-hogg1 Interactionsmentioning

confidence: 65%

Role of XRCC1 in the Coordination and Stimulation of Oxidative DNA Damage Repair Initiated by the DNA Glycosylase hOGG1

Marsin

Vidal

Sossou

et al. 2003

Journal of Biological Chemistry

220

163

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XRCC1 participates in DNA single strand break and base excision repair (BER) to preserve genetic stability in mammalian cells. XRCC1 participation in these pathways is mediated by its interactions with several of the acting enzymes. Here, we report that XRCC1 interacts physically and functionally with hOGG1, the human DNA glycosylase that initiates the repair by BER of the mutagenic oxidized base 8-oxoguanine. This interaction leads to a 2-to 3-fold stimulation of the DNA glycosylase activity of hOGG1. XRCC1 stimulates the formation of the hOGG1 Schiff-base DNA intermediate without interfering with the endonuclease activity of APE1, the second enzyme in the pathway. On the contrary, the stimulation in the appearance of the incision product seems to reflect the addition of the effects of XRCC1 on the two first enzymes of the pathway. The data presented support a model by which XRCC1 will pass on the DNA intermediate from hOGG1 to the endonuclease APE1. This results in an acceleration of the overall repair process of oxidized purines to yield an APE1-cleaved abasic site, which can be used as a substrate by DNA polymerase ␤. More importantly, the results unveil a highly coordinated mechanism by which XRCC1, through its multiple protein-protein interactions, extends its orchestrating role from the base excision step to the resealing of the repaired DNA strand.A major threat to genetic stability is the damaging of DNA by either endogenous or exogenous compounds. This is underscored by the cancer-prone phenotype of human cells defective in DNA repair processes. Exposure of the cellular DNA to reactive oxygen species (ROS), 1 generated either by the normal metabolism of the cell or by chemical and physical exogenous agents, is at the origin of lesions that can have genotoxic or mutagenic consequences. To avoid the effects of ROS and, therefore, to maintain the integrity of their genetic information, organisms have evolved multiple DNA repair mechanisms (1). Because of its capacity to pair with an adenine during replication, 7,8-dihydro-8-oxoguanine (8-oxoG), an oxidized derivative of guanine, is arguably the major mutagenic lesion in DNA. Indeed, in Escherichia coli, the inactivation of the genes involved in the repair of this oxidized base leads to one of the strongest spontaneous mutator phenotypes, characterized by the exclusive increase in G to T transversions. Like for other ROS-induced modifications of DNA, 8-oxoG is mainly repaired by the base excision repair (BER) pathway. This pathway is initiated by the recognition and excision of the oxidized guanine by a DNA glycosylase, OGG1 being the major one in yeast and mammalian cells (2). In human cells, the resulting abasic (apurinic/apyrimidinic (AP)) site can be cleaved by a second enzymatic activity of the hOGG1 polypeptide, namely an AP lyase activity. If such a reaction takes place, the nick produced has a 3Ј-open aldehyde residue that is supposed to be removed by the 3Ј-deoxyribose phosphatase activity of APE1, the major AP endonuclease. However, recent data s...

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Section: Xrcc1-hogg1 Interactionsmentioning

confidence: 65%

Role of XRCC1 in the Coordination and Stimulation of Oxidative DNA Damage Repair Initiated by the DNA Glycosylase hOGG1

Marsin

Vidal

Sossou

et al. 2003

Journal of Biological Chemistry

220

163

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“…XRCC1 has been shown to be multiply phosphorylated in vivo and to exhibit altered phosphorylation patterns following treatment with the DNA-damaging agent methylmethane sulfonate (43). The phosphorylation sites of XRCC1 reside in two spans of residues (459 -494 and 503-546) that coincide with the linker between X1BRCTa and X1BRCTb (44).…”

Section: Discussionmentioning

confidence: 99%

Specificity of Protein Interactions Mediated by BRCT Domains of the XRCC1 DNA Repair Protein

Beernink

Hwang

Ramirez

et al. 2005

Journal of Biological Chemistry

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Protein interactions critical to DNA repair and cell cycle control systems are often coordinated by modules that belong to a superfamily of structurally conserved BRCT domains. Because the mechanisms of BRCT interactions and their significance are not well understood, we sought to define the affinity and specificity of those BRCT modules that orchestrate base excision repair and single-strand break repair. Common to these pathways is the essential XRCC1 DNA repair protein, which interacts with at least nine other proteins and DNA. Here, we characterized the interactions of four purified BRCT domains, two from XRCC1 and their two partners from DNA ligase III␣ and poly(ADP-ribosyl) polymerase 1. A monoclonal antibody was selected that recognizes the ligase III␣ BRCT domain, but not the other BRCT domains, and was used to capture the relevant ligase III␣ BRCT complex. To examine the assembly states of isolated BRCT domains and pairwise domain complexes, we used size-exclusion chromatography coupled with on-line light scattering. This analysis indicated that isolated BRCT domains form homo-oligomers and that the BRCT complex between the C-terminal XRCC1 domain and the ligase III␣ domain is a heterotetramer with 2:2 stoichiometry. Using affinity capture and surface plasmon resonance methods, we determined that specific heteromeric interactions with high nanomolar dissociation constants occur between pairs of cognate BRCT domains. A structural model for a XRCC1⅐DNA ligase III␣ heterotetramer is proposed as a core base excision repair complex, which constitutes a scaffold for higher order complexes to which other repair proteins and DNA are brought into proximity.

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“…Expression of wild-type XRCC1 protein complements the MMS and EMS hypersensitivity phenotype of both EM9 cells [33,52,53,90,91] and XRCC1 -/-mouse fibroblasts [73] (Figure 2A). The high degree of EMS and MMS hypersensitivity indicates that XRCC1 is essential for resistance of cells to the cytotoxic effects of these simple for 1 h, (B) TMZ for 4 h, (C) hmdUrd for 24 h, or (D) camptothecin for 24 h. Cell sensitivity was determined by growth inhibition assays as described [119].…”

Section: Characteristics Of Xrcc1-and Pol β-Deficient Cells: Hypersenmentioning

confidence: 99%

“…A defect in repair of MMS-induced SSBs has been demonstrated by the alkaline comet assay (which will detect cytotoxic abasic sites and SSB intermediates of BER) in XRCC1-deficient CHO cells [33,52,91]. Following a short exposure of mouse embryonic fibroblasts to ice cold MMS, higher levels of DNA damage were seen than found in control untreated cells (NT), but levels were similar in the paired isogenic repair-deficient and wild-type cell lines (Figure 4, panels A and B).…”

Section: Characteristics Of Xrcc1-and Pol β-Deficient Cells: Hypersenmentioning

confidence: 99%

XRCC1 and DNA polymerase β in cellular protection against cytotoxic DNA single-strand breaks

et al. 2008

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Single-strand breaks (SSBs) can occur in cells either directly, or indirectly following initiation of base excision repair (BER). SSBs generally have blocked termini lacking the conventional 5′-phosphate and 3′-hydroxyl groups and require further processing prior to DNA synthesis and ligation. XRCC1 is devoid of any known enzymatic activity, but it can physically interact with other proteins involved in all stages of the overlapping SSB repair and BER pathways, including those that conduct the rate-limiting end-tailoring, and in many cases can stimulate their enzymatic activities.

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Independent roles of XRCC1’s two BRCT motifs in recovery from methylation damage

Cited by 38 publications

References 25 publications

Role of XRCC1 in the Coordination and Stimulation of Oxidative DNA Damage Repair Initiated by the DNA Glycosylase hOGG1

Role of XRCC1 in the Coordination and Stimulation of Oxidative DNA Damage Repair Initiated by the DNA Glycosylase hOGG1

Specificity of Protein Interactions Mediated by BRCT Domains of the XRCC1 DNA Repair Protein

XRCC1 and DNA polymerase β in cellular protection against cytotoxic DNA single-strand breaks

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