PARP10 deficiency manifests by severe developmental delay and DNA repair defect

Shahrour, Maher; Nicolae, Claudia M.; Edvardson, Simon; Ashhab, Motee; Galvan, Adri M.; Constantin, Daniel; Abu‐Libdeh, Bassam; Moldovan, George‐Lucian; Elpeleg, Orly

doi:10.1007/s10048-016-0493-1

Cited by 20 publications

(23 citation statements)

References 16 publications

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“…We observed nonsense and missense mutations in the ubiquitin-interacting motif of PARP10 . As PARP10 deficiency leads to severe DNA repair defects 41 , these mutations may disturb DNA repair in T-PLL. Ten of fourteen patients (71%) displayed gains involving the PARP10 gene.…”

Section: Discussionmentioning

confidence: 99%

SAMHD1 is recurrently mutated in T-cell prolymphocytic leukemia

Johansson

Klein-Hitpaß

Choidas

et al. 2018

Blood Cancer Journal

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T-cell prolymphocytic leukemia (T-PLL) is an aggressive malignancy with a median survival of the patients of less than two years. Besides characteristic chromosomal translocations, frequent mutations affect the ATM gene, JAK/STAT pathway members, and epigenetic regulators. We here performed a targeted mutation analysis for 40 genes selected from a RNA sequencing of 10 T-PLL in a collection of 28 T-PLL, and an exome analysis of five further cases. Nonsynonymous mutations were identified in 30 of the 40 genes, 18 being recurrently mutated. We identified recurrently mutated genes previously unknown to be mutated in T-PLL, which are SAMHD1, HERC1, HERC2, PRDM2, PARP10, PTPRC, and FOXP1. SAMHD1 regulates cellular deoxynucleotide levels and acts as a potential tumor suppressor in other leukemias. We observed destructive mutations in 18% of cases as well as deletions in two further cases. Taken together, we identified additional genes involved in JAK/STAT signaling (PTPRC), epigenetic regulation (PRDM2), or DNA damage repair (SAMHD1, PARP10, HERC1, and HERC2) as being recurrently mutated in T-PLL. Thus, our study considerably extends the picture of pathways involved in molecular pathogenesis of T-PLL and identifies the tumor suppressor gene SAMHD1 with ~20% of T-PLL affected by destructive lesions likely as major player in T-PLL pathogenesis.

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Section: Discussionmentioning

confidence: 99%

SAMHD1 is recurrently mutated in T-cell prolymphocytic leukemia

Johansson

Klein-Hitpaß

Choidas

et al. 2018

Blood Cancer Journal

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“…Indeed, many DNA repair-related syndromes, such as ataxia telangiectasia (ATM mutations), exhibit clinical characteristics that include neurodegeneration (Rass et al, 2007). More recently, homozygous missense mutations in the PCNA binding partners TRAIP and PARP10 have been associated with microcephaly (Harley et al, 2016; Shahrour et al, 2016). Similar to the PCNA mutations, cells from these patients show a strong DNA repair defect but a relatively minor proliferation defect.…”

Section: Pcna and Human Diseasementioning

confidence: 99%

Forging Ahead through Darkness: PCNA, Still the Principal Conductor at the Replication Fork

2017

Self Cite

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Proliferating Cell Nuclear Antigen (PCNA) lies at the center of the faithful duplication of eukaryotic genomes. With its distinctive doughnut-shaped molecular structure, PCNA was originally studied for its role in stimulating DNA polymerases. However, we now know that PCNA does much more than promote processive DNA synthesis. Because of the complexity of the events involved, cellular DNA replication poses major threats to genomic integrity. Whatever predicament lies ahead for the replication fork, PCNA is there to orchestrate the events necessary to handle it. Through its many protein interactions and various post-translational modifications, PCNA has far-reaching impacts on a myriad of cellular functions.

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“…Mutations in PARP10 lead to a neurodegenerative disorder associated with developmental delay and cortical atrophy, as well as delayed myelination (Shahrour et al, 2016). Although a defect in PARP10-dependent Wnt or NFkB signalling was not determined, patient cells had a DNA repair defect in response to hydroxyurea (HU) and ultraviolet light (UV), and the pathology is reminiscent of other DNA repair disorders (Shahrour et al, 2016). A more detailed understanding of the cellular consequences of PARP10 loss and which of its many functions is most important to prevent disease onset and progression will be critical to suggest possible therapeutic avenues for this disease.…”

Section: Adp-ribosylation In Genetic Neurodegenerative Disordersmentioning

confidence: 99%

ADP-ribosylation: from molecular mechanisms to human disease

Hoch

Polo

2020

Genet. Mol. Biol.

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Post-translational modification of proteins by ADP-ribosylation, catalysed by poly (ADP-ribose) polymerases (PARPs) using NAD + as a substrate, plays central roles in DNA damage signalling and repair, modulates a range of cellular signalling cascades and initiates programmed cell death by parthanatos. Here, we present mechanistic aspects of ADP-ribose modification, PARP activation and the cellular functions of ADP-ribose signalling, and discuss how this knowledge is uncovering therapeutic avenues for the treatment of increasingly prevalent human diseases such as cancer, ischaemic damage and neurodegeneration.The PARP1 active site is formed between the catalytic domain (ART domain) and the helical domain (HD) Figure 1 -Schematic mechanism of ADP ribosylation reaction and the catalytic domain of DNA-dependant PARPs. A) A simplified overview of the (ADP)-ribosylation reactions catalysed by PARPs. The final products depend on the acceptor residue acting as a nucleophile (Nu, in blue). PARP1 active-site residues interacting with the ribose-nicotinamide moiety of NAD + are illustrated in orange. B) The NAD + (modelled based on the human PARP1 bound to benzamide adenine dinucleotide [PDB: 6BHV], carbon atoms in yellow) in an extended conformation, bound to the catalytic domain of human PARP1 (ART in cartoon, orange, [PDB: 6BHV]). The residues involved in the catalysis are presented as sticks. C) Superposed cartoon view of human PARP-1 ART domain (orange, [PDB: 6BHV]), PARP1 (light blue, [PDB: 5WS1]) and PARP2 (green, [PDB: 3KJD]) showing the structure of the entire catalytic domains (ART and HD). The modelled NAD + (in yellow) denotes the donor site, while a molecule of ADP (modelled by superimposing the structures of chicken PARP1 [PDB: 1A26] to the human PARP1 [PDB: 3KJD]) indicates the acceptor site. Donor loop (D-loop) and acceptor loop are labelled. D) Surface representation of human PARP1 [PDB: 3KJD] with NAD + modelled into the active site. The ribose group to be attacked is exposed to the solvent. ADP-ribose mechanisms and disease 3 ADP-ribose mechanisms and disease 13

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PARP10 deficiency manifests by severe developmental delay and DNA repair defect

Cited by 20 publications

References 16 publications

SAMHD1 is recurrently mutated in T-cell prolymphocytic leukemia

SAMHD1 is recurrently mutated in T-cell prolymphocytic leukemia

Forging Ahead through Darkness: PCNA, Still the Principal Conductor at the Replication Fork

ADP-ribosylation: from molecular mechanisms to human disease

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