Macrodomain-containing proteins: regulating new intracellular functions of mono(ADP-ribosyl)ation

Feijs, Karla L. H.; Forst, Alexandra; Verheugd, Patricia; Lüscher, Bernhard

doi:10.1038/nrm3601

Cited by 129 publications

(164 citation statements)

References 97 publications

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“…To date, it is not known if PARP10, or protein MARylation, directly participate in DNA repair (29). Here we show that PARP10 specifically binds to ubiquitinated PCNA and participates in PCNA-mediated translesion synthesis.…”

mentioning

confidence: 69%

The ADP-ribosyltransferase PARP10/ARTD10 Interacts with Proliferating Cell Nuclear Antigen (PCNA) and Is Required for DNA Damage Tolerance

Nicolae

Aho

Vlahos

et al. 2014

Journal of Biological Chemistry

103

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Background: PCNA mono-ubiquitination at stalled replication forks recruits translesion synthesis polymerases for fork restart. Results:The mono-ADP-ribosyltransferase PARP10 interacts with PCNA through a PIP-box. PARP10 knockdown results in DNA damage hypersensitivity and defective translesion synthesis. Conclusion: PARP10 participates in PCNA-dependent DNA damage tolerance. Significance: This is the first time that post-translational modification by mono-ADP-ribosylation is implicated in DNA repair.

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mentioning

confidence: 69%

The ADP-ribosyltransferase PARP10/ARTD10 Interacts with Proliferating Cell Nuclear Antigen (PCNA) and Is Required for DNA Damage Tolerance

Nicolae

Aho

Vlahos

et al. 2014

Journal of Biological Chemistry

103

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“…proteins or NAD + metabolites (for detailed overviews see [2,4,5]). PARPs are involved in DNA repair processes, transcriptional regulation, cell death in oxidative stress related pathologies, and metabolic and immune regulation [6].…”

Section: Glossarymentioning

confidence: 99%

“…Several PARG isoforms exist, due to alternative splicing, that can be found in most cellular compartments [9]. Besides PARG, ADP-ribosylacceptor hydrolase 3 (ARH3), ADP-ribosyl lyase and macrodomain-containing proteins are also important regulators of cellular PAR levels [2,5,[9][10][11]. ADPR can be further metabolized to AMP by nucleoside diphosphate linked to X (NUDIX) pyrophosphatases [12].…”

Section: Glossarymentioning

confidence: 99%

“…The interaction between the PI3K pathway and PARPs can be implicated in Warburg-type metabolic rearrangements, as PARP inhibitors and PI3K pathway inhibitors can potentiate each other's antitumor activities [75,82]. Furthermore, it is conceivable that tankyrases or PARP-10 may also have anti-Warburg properties through inducing mitochondrial activity, since these enzymes interact with GSK3 or c-myc [5,37]. The contribution of the anti-Warburg effect of PARP inhibition in cancer treatment is an open question to be investigated.…”

Section: Q6mentioning

confidence: 99%

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Poly(ADP-ribose) polymerases as modulators of mitochondrial activity

Bai

Nagy

Fodor

et al. 2015

Trends in Endocrinology & Metabolism

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Activation of poly(ADP-ribose) polymerases-1 and -2 (PARP-1 and PARP-2) deteriorates mitochondrial activity. NAD + and ATP degradation are not coupled to each other upon PARP activation. PARPs interact with transcription factors modulating mitochondrial activity. PARPs can be positive regulators of mitochondrial output under sublethal stress. PARP inhibition is an attractive target for treating mitochondrial dysfunction.

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“…MACROD2 belongs to a family of genes containing a macro domain, an evolutionarily conserved protein motif (18), whose functional role until recently has been unclear. Studies have demonstrated that MACROD2 deacetylates O-acetyl-ADP ribose, a signaling molecule generated by the deacetylation of acetylated lysine residues in histones and other proteins (19).…”

mentioning

confidence: 99%

MACROD2 overexpression mediates estrogen independent growth and tamoxifen resistance in breast cancers

Mohseni

Cidado

Croessmann

et al. 2014

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

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Tamoxifen is effective for treating estrogen receptor-alpha (ER) positive breast cancers. However, few molecular mediators of tamoxifen resistance have been elucidated. Here we describe a previously unidentified gene, MACROD2 that confers tamoxifen resistance and estrogen independent growth. We found MACROD2 is amplified and overexpressed in metastatic tamoxifen-resistant tumors. Transgene overexpression of MACROD2 in breast cancer cell lines results in tamoxifen resistance, whereas RNAi-mediated gene knock down reverses this phenotype. MACROD2 overexpression also leads to estrogen independent growth in xenograft assays. Mechanistically, MACROD2 increases p300 binding to estrogen response elements in a subset of ER regulated genes. Primary breast cancers and matched metastases demonstrate MACROD2 expression can change with disease evolution, and increased expression and amplification of MACROD2 in primary tumors is associated with worse overall survival. These studies establish MACROD2 as a key mediator of estrogen independent growth and tamoxifen resistance, as well as a potential novel target for diagnostics and therapy.breast cancer | tamoxifen | resistance | MACROD2 | ER positive T he selective estrogen receptor modulator (SERM) tamoxifen is a highly effective drug for the prevention and treatment of estrogen receptor-alpha (ER) positive breast cancers (1). However, resistance to this drug remains a clinically important problem. The molecular mediators of tamoxifen resistance have not been fully elucidated. In part, this is due to the heterogeneous nature of breast cancers, resulting in multiple mechanisms of resistance. For example, past studies have demonstrated that tamoxifen resistance is mediated by differential expression of nuclear hormone receptor coregulators (2, 3), growth factor signaling crosstalk (4-7), regulation of microRNAs (8), cyclin dependent kinases (CKDs) (9), CDK inhibitors (10, 11), and more recently, acquired somatic mutations and alterations in ER (12-17). Further insight into the molecular mediators of tamoxifen and hormone therapy resistance would have great impact on the ability to target genes and pathways that could overcome drug resistance and lead to improved clinical outcomes.In this study we describe a previously unidentified gene, MACROD2, which is amplified and overexpressed in a subset of breast cancers. MACROD2 belongs to a family of genes containing a macro domain, an evolutionarily conserved protein motif (18), whose functional role until recently has been unclear. Studies have demonstrated that MACROD2 deacetylates O-acetyl-ADP ribose, a signaling molecule generated by the deacetylation of acetylated lysine residues in histones and other proteins (19). More recent work demonstrates that MACRO domain containing proteins are involved with mono-ADP ribosylation, and can regulate cell signaling pathways and modify proteins involved with gene transcription (20). Interestingly, MACROD1 (LRP16) has been implicated in modulating ER and androgen receptor (AR) signaling in prio...

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Macrodomain-containing proteins: regulating new intracellular functions of mono(ADP-ribosyl)ation

Cited by 129 publications

References 97 publications

The ADP-ribosyltransferase PARP10/ARTD10 Interacts with Proliferating Cell Nuclear Antigen (PCNA) and Is Required for DNA Damage Tolerance

The ADP-ribosyltransferase PARP10/ARTD10 Interacts with Proliferating Cell Nuclear Antigen (PCNA) and Is Required for DNA Damage Tolerance

Poly(ADP-ribose) polymerases as modulators of mitochondrial activity

MACROD2 overexpression mediates estrogen independent growth and tamoxifen resistance in breast cancers

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