Systemic inflammatory response syndrome in patients undergoing transcatheter aortic valve implantation.

BACKGROUND: Data on systemic inflammatory response syndrome (SIRS) after transcatheter aortic valve implantation (TAVI) are scarce and limited to small cohorts. We aimed to investigate its incidence and mid-term impact in a large cohort of TAVI patients. METHODS: From January 2018 to December 2020, 717 patients with severe aortic valve stenosis undergoing TAVI were included. SIRS was defined as fulfilling at least two of the following criteria within 48 h from the procedure: leucocyte count >12.0 or <4.0 × 109/l, respiratory rate > 20 breaths per minute or PaCO2 ≤ 4.3 kPa/32 mmHg, heart rate > 90 beats per minute and temperature > 38.0 °C or <36.0 °C. Clinical endpoints were 1-year rehospitalization for chronic heart failure (CHF) and 2-years all-cause mortality. Event rates during follow-up were calculated as Kaplan-Meier estimates. RESULTS: SIRS developed in 56.3 % (404/717) of patients after TAVI. SIRS occurred more frequently in patients with post-dilatation (SIRS 34.7 % (140/404) vs. no SIRS 23.3 % (73/313); p < 0.001) and major vascular complications (SIRS 16.1 % (65/404) vs. no SIRS 8.6 % (27/313); p = 0.004). Further, ICU days were more in patients who developed SIRS (SIRS 1.56 ± 1.50 days vs. no SIRS 1.22 ± 1.02 days; p = 0.001). At 2-years, all-cause mortality in the entire population was 23.9 %. However, there was no difference in CHF at 1-year (5.9 % vs. 4.1 %; log-rank = 0.347) nor in all-cause mortality at 2-years (22.0 % vs. 26.2 %; log-rank = 0.690) between the groups. CONCLUSIONS: SIRS is a common finding after TAVI, which may prolong hospital stay but is without effect on mortality during 2-years follow-up.

HPF1-dependent histone ADP-ribosylation triggers chromatin relaxation to promote the recruitment of repair factors at sites of DNA damage.

Poly(ADP-ribose) polymerase 1 (PARP1) activity is regulated by its co-factor histone poly(ADP-ribosylation) factor 1 (HPF1). The complex formed by HPF1 and PARP1 catalyzes ADP-ribosylation of serine residues of proteins near DNA breaks, mainly PARP1 and histones. However, the effect of HPF1 on DNA repair regulated by PARP1 remains unclear. Here, we show that HPF1 controls prolonged histone ADP-ribosylation in the vicinity of the DNA breaks by regulating both the number and length of ADP-ribose chains. Furthermore, we demonstrate that HPF1-dependent histone ADP-ribosylation triggers the rapid unfolding of chromatin, facilitating access to DNA at sites of damage. This process promotes the assembly of both the homologous recombination and non-homologous end joining repair machineries. Altogether, our data highlight the key roles played by the PARP1/HPF1 complex in regulating ADP-ribosylation signaling as well as the conformation of damaged chromatin at early stages of the DNA damage response.

Serine-linked PARP1 auto-modification controls PARP inhibitor response.

Poly(ADP-ribose) polymerase 1 (PARP1) and PARP2 are recruited and activated by DNA damage, resulting in ADP-ribosylation at numerous sites, both within PARP1 itself and in other proteins. Several PARP1 and PARP2 inhibitors are currently employed in the clinic or undergoing trials for treatment of various cancers. These drugs act primarily by trapping PARP1 on damaged chromatin, which can lead to cell death, especially in cells with DNA repair defects. Although PARP1 trapping is thought to be caused primarily by the catalytic inhibition of PARP-dependent modification, implying that ADP-ribosylation (ADPr) can counteract trapping, it is not known which exact sites are important for this process. Following recent findings that PARP1- or PARP2-mediated modification is predominantly serine-linked, we demonstrate here that serine ADPr plays a vital role in cellular responses to PARP1/PARP2 inhibitors. Specifically, we identify three serine residues within PARP1 (499, 507, and 519) as key sites whose efficient HPF1-dependent modification counters PARP1 trapping and contributes to inhibitor tolerance. Our data implicate genes that encode serine-specific ADPr regulators, HPF1 and ARH3, as potential PARP1/PARP2 inhibitor therapy biomarkers.

HPF1 completes the PARP active site for DNA damage-induced ADP-ribosylation.

The anti-cancer drug target poly(ADP-ribose) polymerase 1 (PARP1) and its close homologue, PARP2, are early responders to DNA damage in human cells1,2. After binding to genomic lesions, these enzymes use NAD+ to modify numerous proteins with mono- and poly(ADP-ribose) signals that are important for the subsequent decompaction of chromatin and the recruitment of repair factors3,4. These post-translational modifications are predominantly serine-linked and require the accessory factor HPF1, which is specific for the DNA damage response and switches the amino acid specificity of PARP1 and PARP2 from aspartate or glutamate to serine residues5-10. Here we report a co-structure of HPF1 bound to the catalytic domain of PARP2 that, in combination with NMR and biochemical data, reveals a composite active site formed by residues from HPF1 and PARP1 or PARP2 . The assembly of this catalytic centre is essential for the addition of ADP-ribose moieties after DNA damage in human cells. In response to DNA damage and occupancy of the NAD+-binding site, the interaction of HPF1 with PARP1 or PARP2 is enhanced by allosteric networks that operate within the PARP proteins, providing an additional level of regulation in the induction of the DNA damage response. As HPF1 forms a joint active site with PARP1 or PARP2, our data implicate HPF1 as an important determinant of the response to clinical PARP inhibitors.

Interplay of Histone Marks with Serine ADP-Ribosylation.

Serine ADP-ribosylation (Ser-ADPr) is a recently discovered protein modification that is catalyzed by PARP1 and PARP2 when in complex with the eponymous histone PARylation factor 1 (HPF1). In addition to numerous other targets, core histone tails are primary acceptors of Ser-ADPr in the DNA damage response. Here, we show that specific canonical histone marks interfere with Ser-ADPr of neighboring residues and vice versa. Most notably, acetylation, but not methylation of H3K9, is mutually exclusive with ADPr of H3S10 in vitro and in vivo. We also broaden the O-linked ADPr spectrum by providing evidence for tyrosine ADPr on HPF1 and other proteins. Finally, we facilitate wider investigations into the interplay of histone marks with Ser-ADPr by introducing a simple approach for profiling posttranslationally modified peptides. Our findings implicate Ser-ADPr as a dynamic addition to the complex interplay of modifications that shape the histone code.