DNA ligase III is critical for mtDNA integrity but not Xrcc1-mediated nuclear DNA repair

Gao, Yankun; Katyal, Sachin; Lee, Youngsoo; Zhao, Jingfeng; Rehg, Jerold E.; Russell, H. R.; McKinnon, Peter J.

doi:10.1038/nature09773

Cited by 159 publications

(160 citation statements)

References 30 publications

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“…Recent studies have discovered that Lig3 deficiency does not result in nuclear DNA repair deficiency but loss of mitochondrial DNA integrity (44)(45)(46). This indicates that in cells with an intact c-NHEJ pathway, essential nuclear repair functions can occur in the absence of Lig3 but that mitochondrial DNA repair is compromised.…”

Section: Discussionmentioning

confidence: 99%

Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma

Newman

Bashllari

et al. 2015

Molecular Cancer Research

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In neuroblastoma, MYCN genomic amplification and segmental chromosomal alterations including 1p or 11q loss of heterozygocity and/or 17q gain are associated with progression and poor clinical outcome. Segmental alterations are the strongest predictor of relapse and result from unbalanced translocations attributable to erroneous repair of chromosomal breaks. Although sequence analysis of affected genomic regions suggests that these errors arise by nonhomologous end-joining (NHEJ) of DNA double-strand breaks (DSB), abnormalities in NHEJ have not been implicated in neuroblastoma pathogenesis. On this basis, the hypothesis that an error-prone mechanism of NHEJ is critical for neuroblastoma cell survival was tested. Plasmid-based DSB repair assays demonstrated efficient NHEJ activity in human neuroblastoma cells with repair products that were error-prone relative to nontransformed cells. Neuroblastoma cells derived from tumorigenic neuroblastic phenotypes had differential DNA repair protein expression patterns compared with nontumorigenic cells. Tumorigenic neuroblastoma cells were deficient in DNA ligase IV (Lig4) and Artemis (DCLRE1C), mediators of canonical NHEJ. Conversely, enzymes required for an error-prone alternative NHEJ pathway (alt-NHEJ), DNA Ligase IIIa (Lig3), DNA Ligase I (Lig1), and PARP1 protein were upregulated. Inhibition of Lig3 and Lig1 led to DSB accumulation and cell death, linking alt-NHEJ to cell survival in neuroblastoma. Neuroblastoma cells demonstrated sensitivity to PARP1 inhibition (PARPi) that paralleled PARP1 expression. In a dataset of human neuroblastoma patient tumors, overexpression of genes encoding alt-NHEJ proteins associated with poor survival.Implications: These findings provide an insight into DNA repair fidelity in neuroblastoma and identify components of the alt-NHEJ pathway as promising therapeutic targets. Mol Cancer Res; 13(3); 470-82. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 99%

Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma

Newman

Bashllari

et al. 2015

Molecular Cancer Research

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“…Our data do not rule out a possible role of Lig3 in A-EJ and CSR. However, given the recent findings regarding the nonessential role of Lig3 in nuclear DNA repair (15,16) and the dispensability of its cofactor XRCC1 in A-EJ shown in this study, it seems more likely that Lig1 is the ligase that operates in A-EJ in the absence of intact NHEJ. Alternatively, both Lig1 and Lig3 may participate in A-EJ, and elimination of either one alone may not reveal a defect.…”

Section: Resultsmentioning

confidence: 85%

“…(13). Although the traditional view of Lig3 in nuclear DNA repair has been recently challenged (15,16), the importance of XRCC1 in SSB repair has been well established.…”

mentioning

confidence: 99%

X-ray repair cross-complementing protein 1 (XRCC1) deficiency enhances class switch recombination and is permissive for alternative end joining

Han

Mao

2012

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

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DNA double-strand breaks (DSBs) are essential intermediates in Ig gene rearrangements: V(D)J and class switch recombination (CSR). In contrast to V(D)J recombination, which is almost exclusively dependent on nonhomologous end joining (NHEJ), CSR can occur in NHEJ-deficient cells via a poorly understand backup pathway (or pathways) often termed alternative end joining (A-EJ). Recently, several components of the single-strand DNA break (SSB) repair machinery, including XRCC1, have been implicated in A-EJ. To determine its role in A-EJ and CSR, Xrcc1 was deleted by targeted mutation in the CSR proficient mouse B-cell line, CH12F3. Here we demonstrate that XRCC1 deficiency slightly increases the efficiency of CSR. More importantly, Lig4 and XRCC1 double-deficient cells switch as efficiently as Lig4-deficient cells, clearly indicating that XRCC1 is dispensable for A-EJ in CH12F3 cells during CSR.A DNA double-strand break (DSB) is one of the most severe forms of DNA damage and can result in chromosome loss or translocations. A variety of endogenous and exogenous sources can induce DSBs, including ionizing radiation, reactive oxygen species, and some chemicals. On the other hand, physiological processes during lymphocyte development such as V(D)J and Ig class switch recombination (CSR) rely on DSBs to rearrange genetic information in somatic cells.V(D)J recombination is a site-specific DNA recombination initiated by the RAG proteins, which are evolved from an ancient DNA transposase. The RAG complex recognizes specific DNA sequences called recombination signal sequences (RSS) and cuts the DNA on one side of the RSS. The ensuing repair of the four DNA ends that are produced from a pair of cleavage events results in joining of subexonic coding fragments to form an exon encoding the antigen-binding domain of a B-or T-cell receptor. In contrast, CSR in antigen-stimulated mature B cells is a regionally specific recombination between two repetitive regions [called switch (S) regions] that precede each of the constant regions (1). Looping out intervening sequences between two S regions allows the expression of a new constant region that was further downstream and results in a switch of Ig class (or isotype) from IgM to IgG, IgE, or IgA (2). CSR is initiated by activation-induced cytidine deaminase (AID) that converts DNA cytosines into uracils at S regions. Through mechanisms that are not yet fully understood, repair of AID-generated uracils in the S region ultimately results in DSBs (2), which serve as critical intermediates in an overall cut-and-paste chromosomal deletion (2).In vertebrate cells, DSB repair mechanisms generally fall into two major categories: homologous recombination (HR) and nonhomologous end joining (NHEJ) (3). HR relies on the presence of another copy of DNA sequences that are highly similar to the one harboring the DSB. Copying genetic information from the intact copy allows high-fidelity repair of the DSB. In complex genomes rich in repetitive DNA sequences, HR is restricted to S and G2 phase of the ce...

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“…[5][6][7] Lig3-null mouse embryos die at ~8.5 dpc and previous attempts to generate Lig3-null cells were unsuccessful, 8 suggesting that Lig3 is required for cell survival. To directly determine whether Lig3 is an essential gene in cells, we developed a pre-emptive complementation strategy in mouse embryonic stem (ES) cells (Fig.…”

Section: Lig3 Is Essential For Cellular Viability Due To Its Role In mentioning

confidence: 99%

“…Consistent with our findings, deletion of Lig3 in the developing nervous system using Nestincre leads to ataxic mice with smaller brains; importantly, mitochondria have an abnormal morphology and a reduced DNA content. 6 Not surprisingly, loss of Lig3 in the heart resulting from Ckmm-cre expression is also problematic. …”

Section: Heterologous Dna Ligases Can Substitute For Lig3 In Mitochonmentioning

confidence: 99%

DNA ligase III

Şimşek

Jasin

2011

Cell Cycle

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Lig1 and Lig4 are found throughout eukaryotes. Lig1 is considered to be the critical ligase during replication of the nuclear genome, while Lig4 is critical for the repair of double-strand breaks (DSBs) by nonhomologous end joining (NHEJ). Lig3 has been implicated both in nuclear DNA repair and in mitochondrial genome maintenance.3,4 Although Lig3 has a more restricted phylogenetic distribution in eukaryotes than the other two ligases, it is found more broadly in eukaryotic groups than originally thought, as will be discussed below. Lig3 is Essential for Cellular Viability due to its Role in MitochondriaRecent work using both cell complementation and tissue-specific deletion in the animal has shed light on the role of Lig3.5-7 Lig3-null mouse embryos die at ~8.5 dpc and previous attempts to generate Lig3-null cells were unsuccessful, 8 suggesting that Lig3 is required for cell survival. To directly determine whether Lig3 is an essential gene in cells, we developed a pre-emptive complementation strategy in mouse embryonic stem (ES) cells (Fig. 1)

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DNA ligase III is critical for mtDNA integrity but not Xrcc1-mediated nuclear DNA repair

Cited by 159 publications

References 30 publications

Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma

Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma

X-ray repair cross-complementing protein 1 (XRCC1) deficiency enhances class switch recombination and is permissive for alternative end joining

DNA ligase III

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