The PARP3- and ATM-dependent phosphorylation of APLF facilitates DNA double-strand break repair

Fenton, Amanda L.; Shirodkar, Purnata; Macrae, Chloe J.; Li, Meng; Koch, Christine

doi:10.1093/nar/gkt134

Cited by 58 publications

(59 citation statements)

References 40 publications

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“…PARP-3 also potentiates NHEJ by enabling the accumulation of APLF at DSBs, which results in the retention of the XRCC4/Lig4 DNA ligation complex required for rapid repair of the DNA breaks (Rulten et al 2011). Furthermore, PARP-3 is required for phosphorylation of APLF at Ser116, an event that facilitates efficient DSB repair (Fenton et al 2013). PARP-3 also associates with other DNA repair factors, such as DNA-PKcs, PARP-1, DNA ligase III, DNA ligase IV, Ku70, and Ku80 (Rouleau et al 2007).…”

Section: Nad + Consumersmentioning

confidence: 99%

PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

2017

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The discovery of poly(ADP-ribose) >50 years ago opened a new field, leading the way for the discovery of the poly(ADP-ribose) polymerase (PARP) family of enzymes and the ADP-ribosylation reactions that they catalyze. Although the field was initially focused primarily on the biochemistry and molecular biology of PARP-1 in DNA damage detection and repair, the mechanistic and functional understanding of the role of PARPs in different biological processes has grown considerably of late. This has been accompanied by a shift of focus from enzymology to a search for substrates as well as the first attempts to determine the functional consequences of site-specific ADP-ribosylation on those substrates. Supporting these advances is a host of methodological approaches from chemical biology, proteomics, genomics, cell biology, and genetics that have propelled new discoveries in the field. New findings on the diverse roles of PARPs in chromatin regulation, transcription, RNA biology, and DNA repair have been complemented by recent advances that link ADP-ribosylation to stress responses, metabolism, viral infections, and cancer. These studies have begun to reveal the promising ways in which PARPs may be targeted therapeutically for the treatment of disease. In this review, we discuss these topics and relate them to the future directions of the field.ADP-ribosylation is a reversible post-translational modification (PTM) of proteins resulting in the covalent attachment of a single ADP-ribose unit [i.e., mono(ADP-ribose) (MAR)] or polymers of ADP-ribose units [i.e., poly(ADP-ribose) (PAR)] on a variety of amino acid residues on target proteins (Gibson and Kraus 2012;Daniels et al. 2015a). This modification is mediated by a diverse group of ADPribosyl transferase (ADPRT) enzymes that use ADP-ribose units derived from β-NAD + to catalyze the ADP-ribosylation reaction. These enzymes include bacterial ADPRTs (e.g., cholera toxin and diphtheria toxin) as well as members of three different protein families in yeast and animals: (1) arginine-specific ecto-enzymes (ARTCs), (2) sirtuins, and (3) PAR polymerases (PARPs) . Surprisingly, a recent study showed that the bacterial toxin DarTG can ADP-ribosylate DNA . How this fits into the broader picture of cellular ADP-ribosylation has yet to be determined.In this review, we focus on the mono(ADP-ribosyl)ation (MARylation) and poly(ADP-ribosyl)ation (PARylation) of glutamate, aspartate, and lysine residues by PARP family members. While many reviews have been written on PARPs in the past decade, we highlight the current trends and ideas in the field, in particular those discoveries that have been published in the past 2-3 years.

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Section: Nad + Consumersmentioning

confidence: 99%

PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

2017

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“…Even in the absence of Aplf, overexpression of XRCC4 and DNA ligase IV leads to NHEJ repair (Rulten et al, 2008). So, APLF accelerates NHEJ by acting as a scaffold in the recruitment of the Ku complexes (Rulten et al, 2008;Fenton et al, 2013;Grundy et al, 2013). Quite expectedly, here, in presence of the 30% remaining APLF protein in Aplf-kd cells, no significant alteration in repair capacity was demonstrated in comparison to controls.…”

Section: Discussionmentioning

confidence: 74%

Histone chaperone APLF regulates induction of pluripotency in murine fibroblasts

Syed

Joseph

Mukherjee³

et al. 2016

Journal of Cell Science

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The authors apologise to the readers for any confusion that this error might have caused. For the first time, we report here that the downregulation of histone chaperone Aprataxin PNK-like factor (APLF) promotes reprogramming by augmenting the expression of E-cadherin (Cdh1), which is implicated in the mesenchymal-to-epithelial transition (MET) involved in the generation of induced pluripotent stem cells (iPSCs) from mouse embryonic fibroblasts (MEFs). Downregulation of APLF in MEFs expedites the loss of the repressive MacroH2A.1 (encoded by H2afy) histone variant from the Cdh1 promoter and enhances the incorporation of active histone H3me2K4 marks at the promoters of the pluripotency genes Nanog and Klf4, thereby accelerating the process of cellular reprogramming and increasing the efficiency of iPSC generation. We demonstrate a new histone chaperone (APLF)-MET-histone modification cohort that functions in the induction of pluripotency in fibroblasts. This regulatory axis might provide new mechanistic insights into perspectives of epigenetic regulation involved in cancer metastasis.

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“…PARP3 is a nuclear protein, and has been shown to be associated with a number of DNA repair factors, including Lig3, Lig4, KU70, KU80 and DNA-PKcs [158]. PARP3 inhibition or depletion slows the rate of DSBR repair at early time points following ionising radiation, and PARP3-deficient cells show mild end-joining defects and sensitivity to radiation, bleomycin and etoposide [17,159,160]. However,…”

Section: Parp3 and Non-homologous End Joiningmentioning

confidence: 99%

“…Aprataxin-and-PNK-like factor (APLF/C2ORF/XIP1/PALF) contains PAR-binding zinc fingers (PBZs), which bind to PAR with high affinity ( [163] see below). Even though recruitment of APLF to SSBs has been shown to be almost entirely dependent on PARP1 [164], recruitment to DSBs shows dependence on both PARP3 activity and KU80 [159,165]. APLF facilitates DSBR via interactions between its FHA domain and XRCC4 [166], and via the KU-binding motif (KBM) in the middle region of APLF [165,167].…”

Section: Parp3mentioning

confidence: 99%

The Role of PARPs in DNA Strand Break Repair

Rulten

Dantzer

Caldecott

2015

Cancer Drug Discovery and Development

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ADP-ribosylation is a post-translational modification in which a target protein becomes modified with monomeric, short chains, or long branching chains of ADP-ribose (ADPR). The process can be carried out by a number of ADP-ribosyltransferases and polymerases (ADP-RTs and PARPs) and the consequences of ribosylation are as diverse and heterogeneous as the products that are formed. In mammalian cells, only three PARPs bind to DNA, and their activity is stimulated by DNA ends. A number of roles for these three PARPs have been characterised, including several functions in DNA repair. The known repertoire of ADPR-binding proteins is vastly expanding, meaning that ribosylation increases the rate and complexity of ways in which DNA is repaired by a number of different ways.

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The PARP3- and ATM-dependent phosphorylation of APLF facilitates DNA double-strand break repair

Cited by 58 publications

References 40 publications

PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

Histone chaperone APLF regulates induction of pluripotency in murine fibroblasts

The Role of PARPs in DNA Strand Break Repair

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