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

Beernink, Peter T.; Hwang, Mona; Ramirez, Melissa; Murphy, Michael; Doyle, Sharon A.; Thelen, Michael P.

doi:10.1074/jbc.m502155200

Cited by 56 publications

(55 citation statements)

References 49 publications

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“…Tandem repeat BRCTs, in particular, have been shown to bind phospho-peptides (22)(23)(24)(25)(26)(27)(28)67). In addition, other BRCT domains appear to homo-or heterodimerize (68). The pol μ BRCT structure is atypical in that it appears to be the first reported (in the literature) BRCT domain structure that is neither part of a tandem grouping nor forms a stable dimer, as demonstrated here for μ-BRCT by 15 N relaxation and light scattering.…”

Section: Comparison To Other Brct Domainsmentioning

confidence: 81%

Solution Structure of Polymerase μ's BRCT Domain Reveals an Element Essential for Its Role in Nonhomologous End Joining

et al. 2007

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The solution structure and dynamics of the BRCT domain from human DNA polymerase μ, implicated in repair of chromosome breaks by nonhomologous end joining (NHEJ), has been determined using NMR methods. BRCT domains are typically involved in protein-protein interactions between factors required for the cellular response to DNA damage. The pol μ BRCT domain is atypical in that, unlike other reported BRCT structures, the pol μ BRCT is neither part of a tandem grouping, nor does it appear to form stable homodimers. Although the sequence of the pol μ BRCT domain has some unique characteristics, particularly the presence of > 10% proline residues, it forms the characteristic αβα sandwich, in which three alpha helices are arrayed around a central four-stranded β-sheet. The structure of helix α1 is characterized by two solvent-exposed hydrophobic residues, F46 and L50, suggesting that this element may play a role in mediating interactions of pol μ with other proteins. Consistent with this argument, mutation of these residues, as well as the proximal, conserved residue R43, specifically blocked the ability of pol μ to efficiently work together with NHEJ factors Ku and XRCC4-ligase IV to join noncomplementary ends together in vitro. The structural, dynamic, and biochemical evidence reported here identifies a functional surface in the pol μ BRCT domain critical for promoting assembly and activity of the NHEJ machinery. Further, the similarity between the interaction regions of the BRCT domains of pol μ and TdT support the conclusion that they participate in NHEJ as alternate polymerases. † This research was supported by an American Association of the Colleges of Pharmacy (AACP) new investigator award (to A.L.L.).

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Section: Comparison To Other Brct Domainsmentioning

confidence: 81%

Solution Structure of Polymerase μ's BRCT Domain Reveals an Element Essential for Its Role in Nonhomologous End Joining

et al. 2007

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“…The BER mechanism can be viewed as a multitude of protein complexes unique to the initiating lesion (Table I), with XRCC1 (in concert with its binding partner LigIIIα) acting as a scaffold to orchestrate the movement of DNA repair intermediates from repair initiation and strand scission (DNA glycosylase and APE1) to gap tailoring (APE1 and/or pol ß) and facilitating repair completion (LigIIIα) through a series of protein interactions [34,111,112]. For example, an interaction between XRCC1 and PNKP, a protein necessary for the initial processing of DNA single-strand break termini into ends that are amenable to re-ligation, was shown to be involved in BER following oxidative stress [58,63].…”

Section: Ber Scaffold Proteins and Post-translational Modificationsmentioning

confidence: 99%

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

Almeida¹,

Sobol²

2007

DNA Repair

383

374

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Base excision repair (BER) proteins act upon a significantly broad spectrum of DNA lesions that result from endogenous and exogenous sources. Multiple sub-pathways of BER (short-path or longpatch) and newly designated DNA repair pathways (e.g., SSBR and NIR) that utilize BER proteins complicate any comprehensive understanding of BER and its role in genome maintenance, chemotherapeutic response, neurodegeneration, cancer or aging. Herein, we propose a unified model of BER, comprised of three functional processes: Lesion Recognition/Strand Scission, Gap Tailoring and DNA Synthesis/Ligation, each represented by one or more multiprotein complexes and coordinated via the XRCC1/DNA Ligase III and PARP1 scaffold proteins. BER therefore may be represented by a series of repair complexes that assemble at the site of the DNA lesion and mediates repair in a coordinated fashion involving protein-protein interactions that dictate subsequent steps or sub-pathway choice. Complex formation is influenced by post-translational protein modifications that arise from the cellular state or the DNA damage response, providing an increase in specificity and efficiency to the BER pathway. In this review, we have summarized the reported BER proteinprotein interactions and protein post-translational modifications and discuss the impact on DNA repair capacity and complex formation.

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“…It is also the site for direct binding to both gapped and nicked DNA, and gapped DNA complexed with POL b (Marintchev et al, 1999). XRCC1 has two BRCT domains, which are weakly conserved motifs first identified in BRCA1, and which mediate protein interactions (Zhang et al, 1998;Taylor et al, 2002;Beernink et al, 2005). BRCT1 is an interactive site for PARP whereas BRCT2 is an interactive binding site for Lig3.…”

Section: Xrcc1 Structurementioning

confidence: 99%

Mouse models of XRCC1 DNA repair polymorphisms and cancer

Ladiges

2006

Oncogene

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DNA damage plays a major role in mutagenesis, carcinogenesis and aging. A gene that is emerging as an essential element in the repair of both damaged bases and single-strand breaks (SSB) is XRCC1. XRCC1 has been shown to have a large number of single-nucleotide polymorphisms (SNPs), several of which are being increasingly studied in cancer epidemiology investigations, in part because of their relative high frequency in the population. Although association trends with specific cancer types have occasionally been shown in a variety of ethnic backgrounds, there are often conflicting reports that weaken any substantial conclusions. The functional significance of these SNPs is still largely unknown. XRCC1 is an excellent prototype to provide a forum for determining how epidemiological cancer association studies with DNA repair gene polymorphisms can be validated or refuted. The focus is on the utilization of in silico data and biochemical studies in cell lines and existing mouse models to help provide a framework for the development of new mutant mouse lines that mimic human polymorphisms. These mouse lines will provide the next generation of mammalian tools for carcinogen exposure studies relevant to human cancer and variations in XRCC1, and provide the basis for investigating groups of genes and polymorphisms in an animal model.

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

Cited by 56 publications

References 49 publications

Solution Structure of Polymerase μ's BRCT Domain Reveals an Element Essential for Its Role in Nonhomologous End Joining

Solution Structure of Polymerase μ's BRCT Domain Reveals an Element Essential for Its Role in Nonhomologous End Joining

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

Mouse models of XRCC1 DNA repair polymorphisms and cancer

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