Poly-ADP-ribosylation signaling during DNA damage repair

Golia, Barbara; Singh, Hari; Timinszky, Gyula

doi:10.2741/4318

Cited by 21 publications

(5 citation statements)

References 98 publications

(172 reference statements)

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“…Both double strand DNA break repair and stalled replication forks invoke homologous recombination (HR) and non-homologous end joining (NHEJ) pathways, and a potential role for PARP1 in these processes further substantiates the rationale for utilization of PARP1 inhibitors in the clinical setting. The functional role of PARP1 in double-stranded DNA break repair has been extensively reviewed elsewhere (Golia et al, 2015; Li and Yu, 2014); briefly, PARP1 binds to double-stranded DNA breaks within milliseconds of the damage event, induces PARylation, and attracts the MRN (Mre11, Rad50, NBS1) complex for homologous HR mediated repair. After double strand DNA break resection, resultant single-strand DNA is bound by Rad51, which facilitates template dependent DNA synthesis.…”

Section: The Role Of Parp1 In Sensing Dna Damage and Facilitating Dnamentioning

confidence: 99%

Chromatin to Clinic: The Molecular Rationale for PARP1 Inhibitor Function

et al. 2015

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Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors were recently shown to have clinical impact in a number of disease settings, particularly as related to cancer therapy, treatment for cardiovascular dysfunction, and suppression of inflammation. The molecular basis for PARP1 inhibitor function is complex, and appears to depend on the dual roles of PARP1 in DNA damage repair and transcriptional regulation. Here, the mechanisms by which PARP-1 inhibitors elicit clinical response are discussed, and strategies for translating the preclinical elucidation of PARP-1 function into advances in disease management are reviewed.

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Section: The Role Of Parp1 In Sensing Dna Damage and Facilitating Dnamentioning

confidence: 99%

Chromatin to Clinic: The Molecular Rationale for PARP1 Inhibitor Function

et al. 2015

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“…Poly(ADP-ribosyl)ation (PARylation) is one of such modifications performed by poly(ADP-ribose) polymerases (PARPs) [ 14 , 15 ]. Phylogenetically ancient PARylation is involved in the regulation of numerous cellular functions, such as DNA repair, replication, transcription, translation, telomere maintenance and chromatin remodeling [ [16] , [17] , [18] , [19] ]. A growing body of evidence demonstrates the link between CTCF PARylation and its biological functions.…”

Section: Introductionmentioning

confidence: 99%

Poly(ADP-ribosyl)ation associated changes in CTCF-chromatin binding and gene expression in breast cells

Pavlaki

Chernukhin

Kita

et al. 2018

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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CTCF is an evolutionarily conserved and ubiquitously expressed architectural protein regulating a plethora of cellular functions via different molecular mechanisms. CTCF can undergo a number of post-translational modifications which change its properties and functions. One such modifications linked to cancer is poly(ADP-ribosyl)ation (PARylation). The highly PARylated CTCF form has an apparent molecular mass of 180 kDa (referred to as CTCF180), which can be distinguished from hypo- and non-PARylated CTCF with the apparent molecular mass of 130 kDa (referred to as CTCF130). The existing data accumulated so far have been mainly related to CTCF130. However, the properties of CTCF180 are not well understood despite its abundance in a number of primary tissues. In this study we performed ChIP-seq and RNA-seq analyses in human breast cells 226LDM, which display predominantly CTCF130 when proliferating, but CTCF180 upon cell cycle arrest. We observed that in the arrested cells the majority of sites lost CTCF, whereas fewer sites gained CTCF or remain bound (i.e. common sites). The classical CTCF binding motif was found in the lost and common, but not in the gained sites. The changes in CTCF occupancies in the lost and common sites were associated with increased chromatin densities and altered expression from the neighboring genes. Based on these results we propose a model integrating the CTCF130/180 transition with CTCF-DNA binding and gene expression changes. This study also issues an important cautionary note concerning the design and interpretation of any experiments using cells and tissues where CTCF180 may be present.

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“…DNA damage caused by a variety of factors are important in the process (12). There have been increasing reports on DNA damage repair and tumor occurrence/development, particularly those investigating the association between PARP and the development of tumors (13). PARP-1 may also be involved in the biological function of tumor cells, including tumor cell proliferation, apoptosis, migration and invasion.…”

Section: Discussionmentioning

confidence: 99%

Inhibitors of PARP-1 exert inhibitory effects on the biological characteristics of hepatocellular carcinoma cells in vitro

Mao

Yang

et al. 2017

Molecular Medicine Reports

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It has been confirmed that the inhibitors of poly ADP-ribose polymerF(^9ase-1 (PARP-1) can inhibit the proliferation, apoptosis and invasion of tumor cells. However, the effects of inhibitors of PARP-1 on hepatocellular carcinoma remain to be elucidated. The aim of the present study was to investigate the effect of three types of PARP-1 inhibitor on the proliferation, apoptosis and migration of hepatocellular carcinoma in vitro. An MTT assay was performed to detect the proliferation of HepG2 cells following treatment with the PARP-1 inhibitors, AG014699, BSI-201 and AZD-2281. Flow cytometry was used to detect the apoptosis of HepG2 cells, Western blot analysis was used to detect the protein expression of Casepase-3, Casepase-8, B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), Bcl-2, phosphatase and tensin homolog (PTEN), tissue inhibitor of metalloproteinase (TIMP) 3 and matrix metalloprotease (MMP) 3. A Transwell assay was performed to detect the migration of HepG2 cells. The results showed that AG014699, BSI-201 and AZD-2281 had an inhibitory effect on the proliferation of HepG2 cells in a time- and concentration-dependent manner. AG014699 at concentrations of 10, 30 and 50 µmol/l, and BSI-201 at concentrations of 20, 40 and 60 µmol/l induced the apoptosis of HepG2 cells, and the apoptotic rates were particularly high at 48 h (31, vs. 0.01%; P<0.01 and 24.12, vs. 0.03%, respectively; P<0.01). The protein expression levels of Caspase 3, Caspase 8, Bax, PTEN and TIMP 3 increased with increasing drug concentrations, whereas the protein levels of Bcl-2 and MMP3 decreased with increasing drug concentrations, and were significantly different compared with those in the control group (P<0.01). In conclusion, AG014699, BSI-201 and AZD-2281 inhibitors of PARP-1 significantly inhibited the proliferation of HepG2 cells, however, AG014699 and BSI-201 demonstrated more sensitivity, induced apoptosis and inhibited migration of the hepatocellular carcinoma cells, which may be associated with alterations of the apoptosis signaling pathway and the expression of proteins associated with migration.

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Poly-ADP-ribosylation signaling during DNA damage repair

Cited by 21 publications

References 98 publications

Chromatin to Clinic: The Molecular Rationale for PARP1 Inhibitor Function

Chromatin to Clinic: The Molecular Rationale for PARP1 Inhibitor Function

Poly(ADP-ribosyl)ation associated changes in CTCF-chromatin binding and gene expression in breast cells

Inhibitors of PARP-1 exert inhibitory effects on the biological characteristics of hepatocellular carcinoma cells in vitro

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