Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.

UniProt release 2021_02

Published April 7, 2021

Headline

With a little help from my friend

One of the early responses to eukaryotic DNA damage is ADP-ribosylation of histones and other proteins in the vicinity of the lesion. This post-translation modification, which is important for the decompaction of chromatin and the recruitment of repair factors, can be catalyzed by two related enzymes: PARP1 or PARP2. In the absence of binding partners, the PARPs catalyze ADP-ribosylation on aspartate or glutamate residues. However, in the context of DNA damage, ADP-ribosylation predominantly occurs on serine residues. The switch in amino acid specificity requires the presence of a protein cofactor HPF1. Its mechanism was unraveled recently through the study of the X-ray crystal structure of the PARP2-HPF1 complex.

Under resting, or low stress conditions, the interaction between PARP1 or PARP2 and HPF1 is limited by an inhibitory domain in PARP. In response to high and acute levels of DNA damage, PARP binds DNA and undergoes conformational changes, the inhibitory domain is unfolded, and the interaction with HPF1 is stabilized. Within the complex, PARP2 and HPF1 form a new joint active site with an HPF1 glutamate residue positioned at the very core of the enzyme. Mutagenesis of this glutamate residue to alanine does not affect HPF1 binding to PARP2, but does impair serine ADP-ribosylation. This glutamate within the active site is thought to allow the deprotonation of the serine residue, making it a favorable target for nucleophilic attack. This step is dispensable when the substrate is an aspartate or glutamate residue that is deprotonated at neutral pH. In addition to its active role in catalysis per se, HPF1 may also participate in substrate recognition. Indeed, a putative peptide-binding canyon may form at the interface of HPF1 and PARP2. This site seems perfectly suited for binding lysine-serine motifs that are highly enriched among serine-ADP-ribosylation substrates in vivo.

This discovery goes beyond the excitement of unraveling a new mechanism in a crucial process in DNA repair. It may also have an impact in a clinical setting. PARP small inhibitors have been approved for the treatment of BRCA-negative breast, ovarian and fallopian tube cancers, and it has been previously shown that human cells lacking HPF1 exhibit sensitivity to DNA damaging agents and PARP inhibition. Therefore it may be of interest to re-evaluate the potency and selectivity of existing PARP inhibitors in the presence of HPF1-PARP1/2 complexes and to develop new drugs that would specifically interfere with HPF1-mediated PARP1/2 activity, but not with PARP1/2 enzymatic activity on non-serine residues.

As of this release, HPF1, PARP1 and PARP2 entries have been updated and are publicly available.

UniProt website news

As of this release, we are using the SwissBioPics library of interactive biological images for the visualization of subcellular location data to enhance the representation of UniProt and Gene Ontology (GO) subcellular location annotations.

SwissBioPics covers cell types from all kingdoms of life - ranging from muscle, neuronal and epithelial cells of animals, to the rods, cocci, clubs, spirals and other more exotic forms of bacteria and archaea. A reusable web component and an API allow website developers to visualize subcellular location data (in the form of GO cellular component or UniProt subcellular location identifiers) on these images. The code and technical documentation are available at npmjs.com.

Examples:

UniProtKB news

Change of evidence codes for combinatorial evidence

When UniProt adopted the Evidence Code Ontology (ECO) in 2014, we chose to use the concepts ECO:0000244 in manual assertions and ECO:0000213 in automatic assertions, respectively, for information inferred from a combination of experimental and computational evidence. These two ECO concepts have in fact a broader meaning that includes combinations of any type of evidence, and meanwhile the ECO has been extended with concepts that exactly reflect our usage. We have therefore replaced ECO:0000244 by ECO:0007744 and ECO:0000213 by ECO:0007829.

Changes to the controlled vocabulary of human diseases

New diseases:

Modified diseases:

Changes to the controlled vocabulary for PTMs

New terms for the feature key 'Modified residue' ('MOD_RES' in the flat file):

  • O-di-AMP-tyrosine
  • O-tri-AMP-tyrosine
  • 5-glutamyl dopamine
  • 5-glutamyl noradrenaline
  • 5-glutamyl serotonin

Modified term for the feature key 'Modified residue' ('MOD_RES' in the flat file):

  • L-isoglutamyl histamine -> 5-glutamyl histamine

Changes in subcellular location controlled vocabulary

New subcellular locations:

Modified subcellular location:

UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

We'd like to inform you that we have updated our Privacy Notice to comply with Europe’s new General Data Protection Regulation (GDPR) that applies since 25 May 2018.

Do not show this banner again