PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways

Wang, Minli; Wu, Wei‐Zhong; Wu, Wenqi; Rosidi, Bustanur; Zhang, Lihua; Wang, Huichen; Iliakis, George

doi:10.1093/nar/gkl840

Cited by 711 publications

(668 citation statements)

References 70 publications

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“…Activation of PARP-1 in response to bleomycin depends on Ku antigen PARP-1 has previously been suggested to have a role in regulating the response of Ku antigen to DSBs PARP-1 activation by bleomycin F Dong et al (Hochegger et al, 2006;Wang et al, 2006). To determine whether Ku might also be important for the activation of PARP-1 subsequent to the DSBs induced by bleomycin, we compared the activity of PARP-1 after treatment in extracts prepared from V79 cells, a hamster embryonic lung fibroblast cell line and V15B cells, a line clonally derived from V79 containing a mutation in the Ku80 gene that leads to the absence of Ku70 and Ku80 (Errami et al, 1996).…”

Section: Resultsmentioning

confidence: 99%

“…Genetic studies have established a role for PARP-1 in HR (Hochegger et al, 2006;Idogawa et al, 2007), whereas biochemical and genetic studies have linked PARP-1 to NHEJ (Schultz et al, 2003;Perrault et al, 2004;Audebert et al, 2006;Wang et al, 2006). PARP-1 has been shown to interact with the NHEJ proteins, Ku antigen and DNA-dependent protein kinase (DNA-PK) with reciprocal modifications and mutual alterations in activity suggested (Ruscetti et al, 1998;Ariumi et al, 1999;Galande and KohwiShigematsu, 1999).…”

Section: Introductionmentioning

confidence: 99%

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Activation of PARP-1 in response to bleomycin depends on the Ku antigen and protein phosphatase 5

Fang¹,

Soubeyrand²,

Haché

2010

Oncogene

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Poly (ADP-ribose) polymerase-1 (PARP-1) has an important role in the cellular response to a broad spectrum of DNA lesions. PARP-1 is strongly activated in response to double-stranded DNA breaks (DSBs), yet its contribution to the DSB response is poorly understood. Here we used bleomycin, a radiomimetic that generates DSBs with high specificity to focus on the response of PARP-1 to DSBs. We report that the induction of PARP-1 activity by bleomycin depends on the Ku antigen, a nonhomologous-DNA-End-Joining factor and protein phosphatase 5 (PP5). PARP-1 activation in response to bleomycin was reduced over 10-fold in Ku-deficient cells, whereas its activation in response to U.V. was unaffected. PARP-1 activation was rescued by reexpression of Ku, but was refractory to manipulation of DNA-dependent protein kinase or ATM. Similarly, PARP-1 activation subsequent to bleomycin was reduced 2-fold on ablation of PP5 and was increased 5-fold when PP5 was overexpressed. PP5 seemed to act directly on PARP-1, as its basal phosphorylation was reduced on overexpression of PP5, and PP5 dephosphorylated PARP-1 in vitro. These results highlight the functional importance of Ku antigen and PP5 for PARP-1 activity subsequent to DSBs.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Activation of PARP-1 in response to bleomycin depends on the Ku antigen and protein phosphatase 5

Fang¹,

Soubeyrand²,

Haché

2010

Oncogene

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“…Poly(ADP-ribosyl)ation of proteins represents one of the earliest responses to DNA damage, modifying chromatin structure in proximity of DNA damage; thus favouring the recruitment of DNA repair machineries, such as the base excision repair that is devoted to the correction of abasic sites and single strand breaks. PARP-1 has also been involved in regulation of the repair of DSBs by NHEJ [22]. Moreover, PARP-1 is required for slowing replication fork progression when replication fork collapse as a result of treatment with DSBs inducing agents [23].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, since poly(ADP-ribose) polymerase (PARP)-1 is involved in NHEJ-mediated repair of DSBs and ensures regulation of replication fork progression by HR on damaged DNA [21][22][23], we analyzed also the sensitivity to APC of colon cancer cell lines stably silenced for PARP-1 expression.…”

Section: Introductionmentioning

confidence: 99%

Common fragile sites in colon cancer cell lines: Role of mismatch repair, RAD51 and poly(ADP-ribose) polymerase-1

Vernole

Muzi

Volpi

et al. 2011

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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t r a c tCommon fragile sites (CFS) are specific chromosomal areas prone to form gaps and breaks when cells are exposed to stresses that affect DNA synthesis, such as exposure to aphidicolin (APC), an inhibitor of DNA polymerases. The APC-induced DNA damage is repaired primarily by homologous recombination (HR), and RAD51, one of the key players in HR, participates to CFS stability. Since another DNA repair pathway, the mismatch repair (MMR), is known to control HR, we examined the influence of both the MMR and HR DNA repair pathways on the extent of chromosomal damage and distribution of CFS provoked by APC and/or by RAD51 silencing in MMR-deficient and -proficient colon cancer cell lines (i.e., HCT-15 and HCT-15 transfected with hMSH6, or HCT-116 and HCT-116/3+6, in which a part of a chromosome 3 containing the wild-type hMLH1 allele was inserted). Here, we show that MMR-deficient cells are more sensitive to APC-induced chromosomal damage particularly at the CFS as compared to MMR-proficient cells, indicating an involvement of MMR in the control of CFS stability. The most expressed CFS is FRA16D in 16q23, an area containing the tumour suppressor gene WWOX often mutated in colon cancer. We also show that silencing of RAD51 provokes a higher number of breaks in MMR-proficient cells with respect to their MMR-deficient counterparts, likely as a consequence of the combined inhibitory effects of RAD51 silencing on HR and MMR-mediated suppression of HR. The RAD51 silencing causes a broader distribution of breaks at CFS than that observed with APC. Treatment with APC of RAD51-silenced cells further increases DNA breaks in MMR-proficient cells. The RNAi-mediated silencing of PARP-1 does not cause chromosomal breaks or affect the expression/distribution of CFS induced by APC. Our results indicate that MMR modulates colon cancer sensitivity to chromosomal breaks and CFS induced by APC and RAD51 silencing.

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“…This indicates that the classical XRCC4/DNA-LigaseIV NHEJ pathway, although certainly involved in CSR, coexists with or can be substituted by another molecular mechanism of DNA end-joining. An alternative (or Backup) DNA end-joining pathway has previously been identified in the absence of the classical (C) NHEJ apparatus (Audebert et al, 2004;Wang et al, 2005aWang et al, , 2006. This alternative pathway, which is also DNA-PK independent, relies on the base excision repair XRCC1/ DNA-LigaseIII complex in place of XRCC4/DNALigaseIV and also involves the Poly(ADP-ribose) polymerase-1 protein as a possible factor ensuring the synapsis of DNA ends.…”

Section: Nhej and Csrmentioning

confidence: 99%

V(D)J and immunoglobulin class switch recombinations: a paradigm to study the regulation of DNA end-joining

et al. 2007

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The immune system is the site of intense DNA damage/ modification, which occur during the development and maturation of B and T lymphocytes. V(D)J recombination is initiated by the Rag1 and Rag2 proteins and the formation of a DNA double-strand break (DNA dsb). This DNA lesion is repaired through the use of the nonhomologous end-joining (NHEJ) pathway, several factors of which have been identified through the survey of immunodeficient conditions in humans and mice. Upon antigenic recognition in secondary lymphoid organs, mature B cells further diversify their repertoire through class switch recombination (CSR). CSR is a region-specific rearrangement process triggered by the activation-induced cytidine deaminase factor and also proceeds through the introduction of DNA dsb. However, unlike V(D)J recombination, CSR does not rely strictly on NHEJ for the repair of the DNA lesion. Instead, CSR, but not V(D)J recombination, requires the major factors of the DNA damage response. V(D)J recombination and CSR thus represent an interesting paradigm to study the regulation among the various DNA repair pathways. Oncogene (2007) 26, 7780-7791; doi:10.1038/sj.onc.1210875 Keywords: V(D)J recombination; class switch recombination; SCID; Artemis; Cernunnos; NHEJ V(D)J recombination and CSR: two rearrangement processes that shape the immune system repertoire B and T lymphocytes respond to foreign pathogens through specialized antigenic receptors, the B-cell receptor and T-cell receptor, respectively. The required diversity of these receptors is ensured by the V(D)J recombination process (Figure 1) which assembles previously scattered Variable (V), Diversity (D) and Joining (J) encoding gene segments through a specialized somatic DNA rearrangement mechanism (Tonegawa, 1983). The reaction is initiated by the lymphoid-specific factors, Rag1 and Rag2, which recognize recombination signal sequences (RSS) that flank all V, D and J gene units and introduce a DNA dsb at the border of the RSS (see Dudley et al. (2005) for a review on V(D)J recombination). The resulting DNA double-strand break (DNA dsb) is resolved by the ubiquitous DNA repair machinery known as non-homologous end-joining (NHEJ). The convergent efforts of scientists in the immunology and DNA repair fields were decisive in defining the various actors and molecular mechanisms of this DNA repair pathway over the years as will be discussed below.The terminal maturation of B lymphocytes, which occurs in germinal centres of secondary lymphoid organs upon antigen recognition, is accompanied by two additional molecular processing of immunoglobulin genes that increase the efficiency of the humoral response: (1) the class switch recombination (CSR, Figure 2) exchanges the immunoglobulin (Ig) constant region (CH), thus modifying the function of the Ig without altering its antigenic specificity (Manis et al., 2002b) and (2) somatic hypermutations are introduced in the Ig variable domains, thus increasing their affinity for antigen (Papavasiliou and Schatz, 2002). These two events ar...

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PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways

Cited by 711 publications

References 70 publications

Activation of PARP-1 in response to bleomycin depends on the Ku antigen and protein phosphatase 5

Activation of PARP-1 in response to bleomycin depends on the Ku antigen and protein phosphatase 5

Common fragile sites in colon cancer cell lines: Role of mismatch repair, RAD51 and poly(ADP-ribose) polymerase-1

V(D)J and immunoglobulin class switch recombinations: a paradigm to study the regulation of DNA end-joining

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