Abstract
The functionality of DNA, RNA and proteins is altered dynamically in response to physiological and pathological cues, partly achieved by their modification. While the modification of ...proteins with ADP-ribose has been well studied, nucleic acids were only recently identified as substrates for ADP-ribosylation by mammalian enzymes. RNA and DNA can be ADP-ribosylated by specific ADP-ribosyltransferases such as PARP1–3, PARP10 and tRNA 2′-phosphotransferase (TRPT1). Evidence suggests that these enzymes display different preferences towards different oligonucleotides. These reactions are reversed by ADP-ribosylhydrolases of the macrodomain and ARH families, such as MACROD1, TARG1, PARG, ARH1 and ARH3. Most findings derive from in vitro experiments using recombinant components, leaving the relevance of this modification in cells unclear. In this Survey and Summary, we provide an overview of the enzymes that ADP-ribosylate nucleic acids, the reversing hydrolases, and the substrates’ requirements. Drawing on data available for other organisms, such as pierisin1 from cabbage butterflies and the bacterial toxin–antitoxin system DarT–DarG, we discuss possible functions for nucleic acid ADP-ribosylation in mammals. Hypothesized roles for nucleic acid ADP-ribosylation include functions in DNA damage repair, in antiviral immunity or as non-conventional RNA cap. Lastly, we assess various methods potentially suitable for future studies of nucleic acid ADP-ribosylation.
The aim of this study was to explore occupational safety in pregnant Croatian healthcare workers (HCWs) during the coronavirus disease 2019 (COVID-19) pandemic. To this end we composed an anonymous ...questionnaire that included pregnancy data, risk assessment and mitigation, and workplace intervention and distributed it to HCWs through social media of their groups and associations. The study includes a total of 173 respondents (71.1 % physicians, 19.7 % nurses, 9.2 % other HCWs) diagnosed with pregnancy in 2020 and 2021. Employers were notified about HCWs’ pregnancy at the eighth (IQR 7.0–11.0) week of pregnancy, which delayed workplace risk assessment and mitigation beyond the first trimester. Only 19.6 % of the participants had the risk assessed and mitigated, mostly on their own initiative (76.5 %). After notifying employers about pregnancy, 37.0 % of participants opted for temporary work incapacity (TWI) due to “pregnancy complications” despite healthy pregnancy, 16.8 % were granted a pregnant worker’s paid leave at the expense of the employer, while 5.8 % continued to work at the same workplace. Nurses used the TWI benefit more frequently than physicians (58.8 % vs 30.1 %, P=0.004). Our findings suggest that occupational safety of pregnant HCWs in Croatia lacks clear-cut and transparent strategies to protect pregnant HCWs, forcing them to misuse the healthcare system.
One of the side-effects of the COVID-19 pandemic is a global change in work ergonomic patterns as millions of people replaced their usual work environment with home to limit the spread of the severe ...acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection. The aim of our cross-sectional pilot study was to identify musculoskeletal pain that may have resulted from this change and included 232 telecommunications company workers of both genders 121 (52.2 %) men aged 23–62 (median 41; interquartile range 33–46 yrs.) and 111 (47.8 %) women aged 23–53 (median 40; interquartile range 33–44) who had been working from home for eight months (from 16 March to 4 December 2020) before they joined the study. The participants were asked to fill in our web-based questionnaire by self-assessing their experience of hand, lower back, and upper back/neck pain while working at home and by describing their work setting and physical activity. Compared to previous work at the office, 90 (39.1 %) participants reported stronger pain in the lower back, 105 (45.7 %) in the upper back/neck, and 63 (27.2 %) in their hands. Only one third did not report any musculoskeletal problems related to work from home. Significantly fewer men than women reported hand, lower back, and upper back/ neck pain (p=0.033, p=0.001 and p=0.013, respectively). Sixty-nine workers (29.9 %) reported to work in a separate room, 75 (32.4 %) worked in a separate section of a room with other household members, whereas 87 (37.7 %) had no separate work space, 30 of whom most often worked in the dining room. Ninety-five participants (40.9 %) had no office desk to work at, and only 75 (32.3 %) used an ergonomic chair. Of those who shared their household with others (N=164), 116 (70.7 %) complained about constant or occasional disturbances. Over a half of all participants (52 %) said that they worked longer hours from home than at work, predominantly women (p=0.05). Only 69 participants (29.9 %) were taking frequent breaks, predominantly older ones (p=0.006). Our findings clearly point to a need to inform home workers how to make more ergonomic use of non-ergonomic equipment, use breaks, and exercise and to inform employers how to better organise working hours to meet the needs of work from home.
Are PARPs promiscuous? Feijs, Karla L H; Žaja, Roko
Bioscience reports,
05/2022, Letnik:
42, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Post-translational modifications exist in different varieties to regulate diverse characteristics of their substrates, ultimately leading to maintenance of cell health. The enzymes of the ...intracellular poly(ADP-ribose) polymerase (PARP) family can transfer either a single ADP-ribose to targets, in a reaction called mono(ADP-ribosyl)ation or MARylation, or multiple to form chains of poly(ADP-ribose) or PAR. Traditionally thought to be attached to arginine or glutamate, recent data have added serine, tyrosine, histidine and others to the list of potential ADP-ribose acceptor amino acids. PARylation by PARP1 has been relatively well studied, whereas less is known about the other family members such as PARP7 and PARP10. ADP-ribosylation on arginine and serine is reversed by ARH1 and ARH3 respectively, whereas macrodomain-containing MACROD1, MACROD2 and TARG1 reverse modification of acidic residues. For the other amino acids, no hydrolases have been identified to date. For many PARPs, it is not clear yet what their endogenous targets are. Better understanding of their biochemical reactions is required to be able to determine their biological functions in future studies. In this review, we discuss the current knowledge of PARP specificity in vitro and in cells, as well as provide an outlook for future research.
•PARPs are present in representatives from all six major eukaryotic supergroups.•Reversible PAR metabolism was established early in eukaryotic evolution.•The last common ancestor of all eukaryotes ...possessed five types of PARP proteins.•PARPs are associated to a large variety of different pathways.
Poly(ADP-ribosyl)ation is a post-translational modification of proteins involved in regulation of many cellular pathways. Poly(ADP-ribose) (PAR) consists of chains of repeating ADP-ribose nucleotide units and is synthesized by the family of enzymes called poly(ADP-ribose) polymerases (PARPs). This modification can be removed by the hydrolytic action of poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribosylhydrolase 3 (ARH3). Hydrolytic activity of macrodomain proteins (MacroD1, MacroD2 and TARG1) is responsible for the removal of terminal ADP-ribose unit and for complete reversion of protein ADP-ribosylation.
Poly(ADP-ribosyl)ation is widely utilized in eukaryotes and PARPs are present in representatives from all six major eukaryotic supergroups, with only a small number of eukaryotic species that do not possess PARP genes. The last common ancestor of all eukaryotes possessed at least five types of PARP proteins that include both mono and poly(ADP-ribosyl) transferases. Distribution of PARGs strictly follows the distribution of PARP proteins in eukaryotic species. At least one of the macrodomain proteins that hydrolyse terminal ADP-ribose is also always present. Therefore, we can presume that the last common ancestor of all eukaryotes possessed a fully functional and reversible PAR metabolism and that PAR signalling provided the conditions essential for survival of the ancestral eukaryote in its ancient environment.
PARP proteins are far less prevalent in bacteria and were probably gained through horizontal gene transfer. Only eleven bacterial species possess all proteins essential for a functional PAR metabolism, although it is not known whether PAR metabolism is truly functional in bacteria. Several dsDNA viruses also possess PARP homologues, while no PARP proteins have been identified in any archaeal genome.
Our analysis of the distribution of enzymes involved in PAR metabolism provides insight into the evolution of these important signalling systems, as well as providing the basis for selection of the appropriate genetic model organisms to study the physiology of the specific human PARP proteins.
Systemic steroids are the most common first-line therapy in sudden sensorineural hearing loss (SSNHL), with significant improvement in hearing outcomes in over 60% of patients. It is unknown why 40% ...of patients do not respond to systemic steroid therapy. Salvage treatment includes intratympanic steroids (ITS) and hyperbaric oxygenation (HBO) therapy, with inconsistent results reported. This study aimed to compare the results of ITS and HBO therapy in patients with SSNHL that previously failed systemic steroid therapy.
This is a comparative retrospective nonrandomized interventional cohort study, enrolling 126 patients with SSNHL. Out of these, 35 patients received HBO therapy, 43 patients received ITS, and 48 patients did not receive any second-line therapy (control group). Pure-tone audiograms were performed before and after the salvage therapy in the IT and HBO groups and at the same time interval in the control group. Study variables included age, time until therapy initiation, tinnitus status, and hearing outcomes, with a cutoff criteria of cumulative >30 dB improvement on all frequencies indicating recovery.
ITS and HBO therapy were associated with statistically significant hearing recovery at all frequencies compared to systemic steroids. The results show an average hearing improvement of 13.6 dB overall frequencies (250 to 8000 Hz) after ITS therapy and 7.4 dB in HBO therapy in comparison to the control group. Presence of significant hearing improvement positively correlated with age, ITS therapy, and HBO therapy. Presence of tinnitus before therapy was negatively correlated with hearing improvement. Patients with tinnitus present at the start of therapy improve 4.67 dB less on average compared to those without tinnitus. ITS therapy significantly reduced tinnitus compared to the other two treatment options. Patients with tinnitus present before therapy significantly improve hearing at low frequencies, compared to the control group.
ITS and HBO therapy show superior hearing results compared to observation alone after failed oral steroid therapy for SSNHL. ITS shows an additional positive impact on tinnitus reduction and shows superior hearing outcomes after salvage therapy.
Healthcare workers (HCWs) are considered to run a higher occupational risk of becoming infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and develop coronavirus disease ...(COVID-19) than the rest of the population. The aim of this study was to describe and analyse the characteristics of work-related COVID-19 in Croatian HCWs. Study participants were HCWs who contacted their occupational physician between 1 May 2020 and 12 November 2020 with a request for the registration of COVID-19 as an occupational disease. All participants filled out our online Occupational COVID-19 in Healthcare Workers Questionnaire. The study included 59 HCWs (median age 45.0, interquartile range 36.0–56.0 years). Most (78 %) were nurses or laboratory technicians, and almost all (94.9 %) worked in hospitals. Hierarchical cluster analysis revealed three clusters of COVID-19-related symptoms: 1) elevated body temperature with general weakness and fatigue, 2) diarrhoea, and 3) headache, muscle and joint pain, anosmia, ageusia, and respiratory symptoms (nasal symptoms, burning throat, cough, dyspnoea, tachypnoea). Almost half (44.6 %) reported comorbidities. Only those with chronic pulmonary conditions were more often hospitalised than those without respiratory disorders (57.1 % vs. 2.5 %, respectively; P=0.001). Our findings suggest that work-related COVID-19 among Croatian HCWs is most common in hospital nurses/laboratory technicians and takes a mild form, with symptoms clustering around three clinical phenotypes: general symptoms of acute infection, specific symptoms including neurological (anosmia, ageusia) and respiratory symptoms, and diarrhoea as a separate symptom. They also support evidence from other studies that persons with chronic pulmonary conditions are at higher risk for developing severe forms of COVID-19.
Coronavirus disease 2019 (COVID-19) can be diagnosed as occupational disease by an occupational health physician (OHP), if supported by relevant work-related and medical documentation. The aim of ...this study was to analyse such documentation submitted by Croatian healthcare workers (HCWs) and discuss its relevance in view of European and Croatian guidelines. The study included 100 Croatian HCWs who were SARS-CoV-2-positive and requested that their infection be diagnosed as occupational disease by their OHPs from 1 May 2020 to 10 March 2021. As participants they were asked to fill out our online Occupational COVID-19 in Healthcare Workers Questionnaire. For the purpose of this study we analysed answers about the type of close contact at the workplace, COVID-19 symptoms, and enclosed work-related (job description, employer statement about exposure to SARS-CoV-2) and medical documentation (positive SARS-CoV-2 polymerase chain reaction test and patient history confirming the diagnosis of COVID-19). Most participants were working in hospitals (N=95), mostly nurses (N=75), who became infected by a patient (N=68) or colleague (N=31), and had at least one COVID-19 symptom (N=87). Eighty participants did not enclose obligatory documents, 41 of whom failed to submit job description and 31 both job description and employer statement. These findings confirm that the major risk of occupational COVID-19 in HCWs is close contact with patients and colleagues, and points out the need for better cooperation between OHPs, occupational safety experts, employers, and diseased workers.
Blowout fractures of the orbit are relatively common injuries of the viscerocranium. However, there is still no general consensus on the optimal timing and method of treatment. This article gives a ...comprehensive review of the pathology of the fracture, process of diagnosis, management and follow-up, including results of a retrospective study done in the Department of Maxillofacial and Oral Surgery, Dubrava University Hospital, Zagreb, in which we collected and analyzed medical records of 91 patients treated for blowout fractures in our institution over a period of three years. Our study showed that the patients admitted to our department more than 48 hours from the injury were more than 4 times likely to develop a complication that would require additional treatment. In other words, of our 91 patients, those admitted to our department in the first 48 hours from the injury had a more than 4 times lower rate of complications, likely due to early recognition of the injury with early intravenous antibiotic and corticosteroid administration, multidisciplinary treatment, and early recognition of candidates for emergency and early surgical treatment. The results of our study show the importance of treating blowout fractures in a tertiary care facility with expertise on the subject.
Post-translational modifications (PTM) of proteins are crucial for fine-tuning a cell's response to both intracellular and extracellular cues. ADP-ribosylation is a PTM, which occurs in two flavours: ...modification of a target with multiple ADP-ribose moieties (poly(ADP-ribosyl)ation or PARylation) or with only one unit (MARylation), which are added by the different enzymes of the PARP family (also known as the ARTD family). PARylation has been relatively well-studied, particularly in the DNA damage response. This has resulted in the development of PARP inhibitors such as olaparib, which are increasingly employed in cancer chemotherapeutic approaches. Despite the fact that the majority of PARP enzymes catalyse MARylation, MARylation is not as well understood as PARylation. MARylation is a dynamic process: the enzymes reversing intracellular MARylation of acidic amino acids (MACROD1, MACROD2, and TARG1) were discovered in 2013. Since then, however, little information has been published about their physiological function. MACROD1, MACROD2, and TARG1 have a 'macrodomain' harbouring the catalytic site, but no other domains have been identified. Despite the lack of information regarding their cellular roles, there are a number of studies linking them to cancer. However, some of these publications oppose each other, some rely on poorly-characterised antibodies, or on aberrant localisation of overexpressed rather than native protein. In this review, we critically assess the available literature on a role for the hydrolases in cancer and find that, currently, there is limited evidence for a role for MACROD1, MACROD2, or TARG1 in tumorigenesis.
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