Poly (ADP-ribose) polymerase 1
| Poly (ADP-ribose) polymerase 1 | ||
|---|---|---|
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| Structure from PARP1 to PDB 1UK0 | ||
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Existing structural data: 1uk0, 1uk1, 1wok, 2cok, 2cr9, 2cs2, 2dmj |
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| Properties of human protein | ||
| Mass / length primary structure | 1013 aa; 113.2 kDa | |
| Identifier | ||
| Gene names | PARP1 ; ADPRT; ADPRT1; PARP; PARP-1; PPOL; pADPRT-1 | |
| External IDs | ||
| Enzyme classification | ||
| EC, category | 2.4.2.30 , glycosyl transferase | |
| Response type | Poly (ADP-ribosyl) ation (60-80x) | |
| Substrate | NAD + + (ADP-D-ribosyl) (n) acceptor | |
| Products | Nicotinamide + (ADP-D-ribosyl) (n + 1) -acceptor | |
| Occurrence | ||
| Parent taxon | Eukaryotes | |
| Orthologue | ||
| human | mouse | |
| Entrez | 142 | 11545 |
| Ensemble | ENSG00000143799 | |
| UniProt | P09874 | |
| Refseq (mRNA) | NM_001618 | NM_007415 |
| Refseq (protein) | NP_001609 | NP_031441 |
| Gene locus | Chr 1: 224.62 - 224.66 Mb | |
| PubMed search | 142 |
11545
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Poly (ADP-Ribose) -Polymerase 1 ( PARP1 ) is an endogenous enzyme that is involved in the repair of single-stranded DNA breaks .
properties
PARP1 is a member of a group of 17 isoenzymes, some of which have different structures and functions in the cell. The PARP gene coding for PARP1 and other PARP isoenzymes is 43 kb long and contains 23 exons . PARP1 consists of 1013 amino acids and has a molar mass of 113.2 kDa . Structurally, PARP1 consists of three domains: a DNA-binding zinc finger domain at the N-terminal end, a middle automodification domain and an NAD-binding domain at the C end.
Cell biology
PARP1 and the other PARP isoenzymes catalyze the ADP-ribosylation of chromatin proteins (such as histone H1 ). This comes into play in particular with single-stranded DNA breaks, initiates the repair of this damage and thus plays an important role in the recovery of the cell after DNA damage. This process is a process that occurs in all eukaryotes and belongs to the area of post-translational modification of proteins. Every single ribosylation step, of which about 60 to 80 take place at an acceptor, consumes one molecule of NAD + . There is therefore a deficiency in this substance in cells with repaired DNA single-strand breaks.
The inhibition of the PARP1 enzyme means that breaks in single-stranded DNA can only be repaired with the help of the repair system for double-stranded DNA breaks with the involvement of the cellular apparatus for homologous recombination . It is therefore possible that cancer cells , in which the homologous recombination is often defective, can be inhibited in their growth or even killed with substances that inhibit PARP1 (see pharmacology).
PARP1 is also active in neurons that are part of long-term memory . In the mouse model it was also found that overexpression of PARP1 and the resulting lack of energy is the mechanism for the toxicity of streptozotocin for pancreatic cells . PARP1-free mice show telomere shortening and lack of stability in the entire genome.
Various other PARP isoenzymes ( PARP2 etc.) are indispensable in the spindle apparatus of the eukaryotic cells.
In various species, cell longevity is correlated with PARP1 activity. The proteolytic degradation of PARP1 by caspase-3 is an intermediate step in programmed cell death ( apoptosis ).
pharmacology
PARP inhibitors are inhibitors of various poly-ADP-ribose-polymerase isoenzymes (e.g. PARP1, PARP2). They are a relatively new, still small group of drugs that are being developed as part of targeted cancer therapy for the treatment of various cancers with defects in the double-stranded DNA repair mechanism (e.g. some forms of ovarian cancer or metastatic breast cancer ). PARP inhibitors prevent cancer cells from causing a z. B. immediately repair single-stranded DNA damage induced by cytostatics, which can then progressively expand to a double-stranded DNA break. In many tumors, especially in those with mutations in BRCA1 or BRCA2 , this can no longer be repaired, so that the tumor cells die off preferentially over body cells because of the accumulation of unrepaired DNA double-strand breaks. PARP inhibitors are currently used primarily as maintenance therapy ("second line") after a primary chemotherapy .
literature
- Christopher J. Lord and Alan Ashworth: PARP inhibitors: Synthetic lethality in the clinic. Review article in: Science . Volume 355, No. 6330, 2017, pp. 1152–1185, doi: 10.1126 / science.aam7344
Web links
- PMC 1525219 (free full text).
- Caffeine breakdown products as PARP-1 inhibitors; PMID 16870158 .
Individual evidence
- ↑ a b c Poly (ADP-ribose) polymerase 1. In: Online Mendelian Inheritance in Man . (English).