PARP1 and PARP2 stabilise replication forks at base excision repair intermediates through Fbh1-dependent Rad51 regulation

Ronson, George E.; Piberger, Ann Liza; Higgs, Martin R.; Olsen, Anna L; Stewart, Grant S.; McHugh, Peter J.; Petermann, Eva; Lakin, Nicholas D.

doi:10.1038/s41467-018-03159-2

Cited by 162 publications

(148 citation statements)

References 61 publications

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“…As in the T cell compartment, B cell lymphopenia in dually PARP-1-and PARP-2-deficient mice is associated with an accumulation of unrepaired DNA damage in proliferating B cells leading to cell death, suggesting a potential model whereby coordinated signals from PARP-1 and PARP-2 are required to maintain genomic integrity during lymphoid proliferation. This is consistent with recent data showing that dual PARP-1 and PARP-2 deficiency results in the accumulation of replication-associated DNA damage due to the impaired stabilization of Rad51 at damaged DNA replication forks and uncontrolled DNA resection thereafter [37].…”

Section: Impact Of Parp-1 and Parp-2 On B Cell Development And Functionsupporting

confidence: 93%

Immunomodulatory Roles of PARP-1 and PARP-2: Impact on PARP-Centered Cancer Therapies

Yélamos

Moreno-Lama

Jimeno

et al. 2020

Cancers

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Poly(ADP-ribose) polymerase-1 (PARP-1) and PARP-2 are enzymes which posttranslationally modify proteins through poly(ADP-ribosyl)ation (PARylation)-the transfer of ADP-ribose chains onto amino acid residues-with a resultant modulation of protein function. Many targets of PARP-1/2-dependent PARylation are involved in the DNA damage response and hence, the loss of these proteins disrupts a wide range of biological processes, from DNA repair and epigenetics to telomere and centromere regulation. The central role of these PARPs in DNA metabolism in cancer cells has led to the development of PARP inhibitors as new cancer therapeutics, both as adjuvant treatment potentiating chemo-, radio-, and immuno-therapies and as monotherapy exploiting cancer-specific defects in DNA repair. However, a cancer is not just made up of cancer cells and the tumor microenvironment also includes multiple other cell types, particularly stromal and immune cells. Interactions between these cells-cancerous and non-cancerous-are known to either favor or limit tumorigenesis. In recent years, an important role of PARP-1 and PARP-2 has been demonstrated in different aspects of the immune response, modulating both the innate and adaptive immune system. It is now emerging that PARP-1 and PARP-2 may not only impact cancer cell biology, but also modulate the anti-tumor immune response. Understanding the immunomodulatory roles of PARP-1 and PARP-2 may provide invaluable clues to the rational development of more selective PARP-centered therapies which target both the cancer and its microenvironment.

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Section: Impact Of Parp-1 and Parp-2 On B Cell Development And Functionsupporting

confidence: 93%

Immunomodulatory Roles of PARP-1 and PARP-2: Impact on PARP-Centered Cancer Therapies

Yélamos

Moreno-Lama

Jimeno

et al. 2020

Cancers

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“…Here, we found that ARTD1 and ARTD2 do not modify the same ADP-ribosylation target proteins in H 2 O 2 -treated HeLa cells, indicating that ARTD2 is likely regulated by a different stress stimulus than ARTD1. Recent observations confirm that ARTD1 and ARTD2 regulate two independent, but intrinsically linked aspects of DNA base damage tolerance by promoting base excision repair directly [24]. Nevertheless, ARTD1 À/À /ARTD2 À/À mice are not viable [25]; thus, it is possible that ARTD1 and ARTD2 functionally compensate for each other indirectly by modifying different target proteins that function in the same cellular processes.…”

Section: Artd1 Is the Main Writer Of Genotoxic Stress-induced Adp-ribmentioning

confidence: 98%

Comprehensive ADP‐ribosylome analysis identifies tyrosine as an ADP‐ribose acceptor site

et al. 2018

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Despite recent mass spectrometry (MS)-based breakthroughs, comprehensive ADP-ribose (ADPr)-acceptor amino acid identification and ADPr-site localization remain challenging. Here, we report the establishment of an unbiased, multistep ADP-ribosylome data analysis workflow that led to the identification of tyrosine as a novel ARTD1/PARP1-dependent ADPr-acceptor amino acid. MS analyses of ADP-ribosylated proteins confirmed tyrosine as an ADPr-acceptor amino acid in RPS3A (Y155) and HPF1 (Y238) and demonstrated that -modification of RPS3A is dependent on HPF1. We provide an ADPr-site Localization Spectra Database (ADPr-LSD), which contains 288 high-quality ADPr-modified peptide spectra, to serve as ADPr spectral references for correct ADPr-site localizations.

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“…In contrast, it has been reported that PARP1 is not involved in the repair of thymidine glycol lesions [53]. BER is responsible for the repair of DNA alkylation damage and PARP1 is essential for the repair of these lesions [55,56]. During BER, PARP1 promotes XRCC1-dependent repair of oxidized purines, but repair of oxidized pyrimidines appears to be PARP1-independent [53].…”

Section: Parp1 and Its Role In Dna Repairmentioning

confidence: 99%

Toward understanding genomic instability, mitochondrial dysfunction and aging

Fakouri

Demarest

et al. 2018

The FEBS Journal

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The biology of aging is an area of intense research, and many questions remain about how and why cell and organismal functions decline over time. In mammalian cells, genomic instability and mitochondrial dysfunction are thought to be among the primary drivers of cellular aging. This review focuses on the interrelationship between genomic instability and mitochondrial dysfunction in mammalian cells and its relevance to age‐related functional decline at the molecular and cellular level. The importance of oxidative stress and key DNA damage response pathways in cellular aging is discussed, with a special focus on poly (ADP‐ribose) polymerase 1, whose persistent activation depletes cellular energy reserves, leading to mitochondrial dysfunction, loss of energy homeostasis, and altered cellular metabolism. Elucidation of the relationship between genomic instability, mitochondrial dysfunction, and the signaling pathways that connect these pathways/processes are keys to the future of research on human aging. An important component of mitochondrial health preservation is mitophagy, and this and other areas that are particularly ripe for future investigation will be discussed.

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PARP1 and PARP2 stabilise replication forks at base excision repair intermediates through Fbh1-dependent Rad51 regulation

Cited by 162 publications

References 61 publications

Immunomodulatory Roles of PARP-1 and PARP-2: Impact on PARP-Centered Cancer Therapies

Immunomodulatory Roles of PARP-1 and PARP-2: Impact on PARP-Centered Cancer Therapies

Comprehensive ADP‐ribosylome analysis identifies tyrosine as an ADP‐ribose acceptor site

Toward understanding genomic instability, mitochondrial dysfunction and aging

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