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Additional file 1: Table S1. Genetic characteristics of the HGSOC cells.

Additional file 4: Table S3. Study population of ovarian cancers tested for CCDC6 protein expression.

Additional file 3: Table S2. H-scores of the CCDC6 immunohistochemical staining.

The poly(ADP-ribose) polymerase (PARP) superfamily of enzymes catalyses the ADP-ribosylation (ADPr) of target proteins by using nicotinamide adenine dinucleotide (NAD+) as a donor. ADPr reactions occur either in the form of attachment of a single ADP-ribose nucleotide unit on target proteins or in the form of ADP-ribose chains, with the latter called poly(ADP-ribosyl)ation. PARPs regulate many cellular processes, including the maintenance of genome stability and signal transduction. In this review, we focus on the PARP family members that possess the ability to modify proteins by poly(ADP-ribosyl)ation, namely PARP1, PARP2, Tankyrase-1, and Tankyrase-2. Here, we detail the cellular functions of PARP1 and PARP2 in the regulation of DNA damage response and describe the function of Tankyrases in Wnt-mediated signal transduction. Furthermore, we discuss how the understanding of these pathways has provided some major breakthroughs in the treatment of human cancer.

Microplastic pollution is presently considered a high concern topic by scientists, policy makers, governmental bodies, non-governmental organizations and the general public. Microplastics are highly widespread in all environmental compartments (e.g. air, water, sediments and biota) and increasing empirical evidence points towards potential negative effects on organisms, both at an individual scale and potentially at population and ecosystem level, as well as effects on human health. To understand the levels and effects of microplastics on biota, it is important to conduct risk assessment evaluations based on realistic microplastic concentration exposure scenarios which are targeted at identifying the effects of microplastics on species and ecosystems. Realistic data on exposures should derive from reliable monitoring data on the uptake and accumulation of microplastics in biota. Presently, there is sufficient empirical data available to underpin arguments to suggest species that could serve as suitable candidates for monitoring microplastics in the environment. Comparison of available data is still limited due to the use of different analytical methods and reporting units, nonetheless researchers have been providing recommendations and frameworks to surpass these limitations. Many methods initially focused on particles

ADP-ribosylation (ADPr) is a posttranslational modification (PTM) of proteins that controls many cellular processes, including DNA repair, transcription, chromatin regulation and mitosis. A number of proteins catalyse the transfer and hydrolysis of ADPr, and also specify how and when the modification is conjugated to the targets. We recently discovered a new form of ADPr that is attached to serine residues in target proteins (Ser-ADPr) and showed that this PTM is specifically made by PARP1/HPF1 and PARP2/HPF1 complexes. In this work, we found by quantitative proteomics that histone Ser-ADPr is reversible in cells during response to DNA damage. By screening for the hydrolase that is responsible for the reversal of Ser-ADPr, we identified ARH3/ADPRHL2 as capable of efficiently and specifically removing Ser-ADPr of histones and other proteins. We further showed that Ser-ADPr is a major PTM in cells after DNA damage and that this signalling is dependent on ARH3. DOI: http://dx.doi.org/10.7554/eLife.28533.001, eLife digest Inside cells, genetic information is stored within molecules of DNA. If any of the DNA becomes damaged, the cell has a suite of proteins that can help to repair the DNA. Many of these proteins act as signals that alert the cell to the presence of damaged DNA. One such signal involves adding a molecule called ADPr onto specific proteins that are near the damaged section of DNA. There are several enzymes that can attach ADPr molecules to proteins and other enzymes known as ADP-ribosylhydrolases can halt the signal by removing the ADPr molecules. Together, these two groups of enzymes control how strong the ADPr signal is, how long it lasts, and therefore control the DNA repair process. Proteins are made up of building blocks called amino acids. Previous studies have shown that ADPr molecules can be attached to several different amino acids including glutamate, aspartate and cysteine. Specific ADP-ribosylhydrolase enzymes are known to be responsible for removing ADPr molecules from these amino acids. In 2016, a group of researchers found that ADPr can also be added to an amino acid called serine. However, it is not known if cells are able to remove ADPr molecules from serine, or which ADP-ribosylhydrolases might be involved. Fontana, Bonfiglio, Palazzo et al. – including some of the researchers involved in the earlier work – used biochemical techniques to investigate if any human enzymes are able to remove ADPr molecules that have been attached to serines on proteins. The experiments reveal that the serine ADPr signal increases after DNA damage, before reducing over time. However, in human cancer cells that lack an ADP-ribosylhydrolase known as ARH3, the serine ADPr signal persists after DNA damage. This suggests that adding ADPr molecules to the amino acid serine is a key signal that controls DNA repair and that ARH3 is the main enzyme responsible for erasing this signal. Drugs that inhibit some of the enzymes that attach ADPr molecules to proteins are used to treat some breast, ovarian and prostate cancers. Therefore, understanding how cells remove these signals from proteins may aid the development of new therapies for these conditions. The next steps following on from this work are to find out more about the structure of ARH3 and to understand how cells that lack this enzyme behave. DOI: http://dx.doi.org/10.7554/eLife.28533.002

Ataxia-Telangiectasia (A-T) is a recessive hereditary syndrome characterized by cerebellar degeneration, telangiectasia, precocious aging, immunodeficiency, cancer predisposition and insulin-resistant diabetes. A-T is caused by defects in Ataxia-Telagiectasia Mutated (Atm) gene. Atm encodes a ser/thr kinase (ATM) of the PI3 kinase family that plays a crucial role in the DNA damage response (DDR). Although some A-T features are easily explained by defects in DDR, others, like precocious aging, insulin-resistant diabetes and the recently described whole chromosome instability, are not. We, thus, searched for possible DDR-independent roles of ATM. To this end, we analyzed human cells in which ATM was chemically or genetically downregulated in the absence of any DNA damaging insult. We observed that ATM downregulation induced abnormal mitotic figures. The phenotypes ranged from abnormal mitotic spindles that were displaced from the cell centre, indicating loss of cortical interaction of astral microtubules, to spindles with extra poles that slowly coalesced to form pseudo-bipolar spindles. Often the extra poles lacked the centrosome marker gamma-tubulin. These alterations resembled that of previously described mitotic phenotypes induced by genetic knock-down of the poly(ADP-ribosyl)-polymerase Tankyrase 1 (TNKS1). The mitotic phenotypes have been ascribed to reduced TNKS1-dependent poly(ADP-ribosyl)ation of the Nuclear and Mitotic Apparatus protein 1 (NuMA1). Indeed, we found that ATM down-regulation impaired mitotic poly(ADP-ribosyl)ation of NuMA1. We further observed that ATM physically interacted with TNKS1. ATM activity was required for TNKS1-dependent poly(ADP-ribosyl)ation of NuMa1, perhaps through ATM-dependent phosphorylation of NuMa1, but not for ATM-TNKS1 interaction. Previous observations have shown that TNKS1 controls telomere length by (poly(ADP-ribosyl)ating TRF1 and glucose uptake by regulating insulin-dependent transport into the plasma-membrane of the glucose transporter Glut-4. We propose that the ATM-dependent control of TNKS1 function, independently of DDR, could explain several A-T features and shed light on new therapeutic approaches for the A-T syndrome.