PARP1

Description

The PARP1 (poly(ADP-ribose) polymerase 1) is a protein-coding gene located on chromosome 1.

Poly [ADP-ribose] polymerase 1 (PARP-1) also known as NAD+ ADP-ribosyltransferase 1 or poly[ADP-ribose] synthase 1 is an enzyme that in humans is encoded by the PARP1 gene. It is the most abundant of the PARP family of enzymes, accounting for 90% of the NAD+ used by the family. PARP1 is mostly present in cell nucleus, but cytosolic fraction of this protein was also reported.

== Function == PARP1 works:

By using NAD+ to synthesize poly ADP ribose (PAR) and transferring PAR moieties to proteins (ADP-ribosylation). In conjunction with BRCA, which acts on double strands; members of the PARP family act on single strands; or, when BRCA fails, PARP takes over those jobs as well (in a DNA repair context). PARP1 is involved in:

Differentiation, proliferation, and tumor transformation Normal or abnormal recovery from DNA damage May be the site of mutation in Fanconi anemia Induction of inflammation. The pathophysiology of type I diabetes. PARP1 is activated by:

Helicobacter pylori in the development and proliferation of gastric cancer.

=== Role in DNA damage repair === PARP1 acts as a first responder that detects DNA damage and then facilitates choice of repair pathway. PARP1 contributes to repair efficiency by ADP-ribosylation of histones leading to decompaction of chromatin structure, and by interacting with and modifying multiple DNA repair factors.

PARP1 is a poly-ADP-ribosyltransferase that mediates poly-ADP-ribosylation of proteins and plays a key role in DNA repair. It catalyzes the transfer of ADP-D-ribosyl groups from NAD+ to target residues, primarily serine, but also glutamate, aspartate, histidine, and tyrosine. This process forms poly-ADP-ribose chains with an average length of 20-30 units. Serine ADP-ribosylation is the primary form of ADP-ribosylation in response to DNA damage. The specificity for different amino acids is determined by interacting factors such as HPF1 and NMNAT1. HPF1 interacts with PARP1 and confers serine specificity by completing the active site, while NMNAT1 interacts with PARP1 and confers glutamate and aspartate specificity. PARP1 initiates DNA repair by recognizing and binding to DNA breaks within chromatin. It recruits HPF1, leading to serine ADP-ribosylation of target proteins like histones, promoting chromatin decompaction and recruitment of repair factors. This process facilitates the repair of DNA strand breaks. HPF1 limits the length of poly-ADP-ribose chains to control polymerase activity. In addition to base excision repair, PARP1 is also involved in double-strand break repair. It accumulates at DNA damage sites with TIMELESS and promotes homologous recombination repair through poly-ADP-ribosylation. PARP1 poly-ADP-ribosylates a range of proteins, including itself, APLF, CHFR, RPA1, and NFAT5. PARP1 can also ADP-ribosylate DNA directly at strand break termini. It is crucial for recruiting PARP9 and DTX3L to DNA damage sites, and the subsequent PARP9-DTX3L-mediated ubiquitination facilitates the rapid and specific recruitment of 53BP1/TP53BP1, UIMC1/RAP80, and BRCA1. PARP1-mediated DNA repair in neurons contributes to sleep regulation. Beyond DNA repair, PARP1 participates in other cellular processes like transcription regulation, programmed cell death, membrane repair, adipogenesis, and innate immunity. It acts as a repressor of transcription by binding to nucleosomes and modulating chromatin structure, similar to histone H1, thereby affecting RNA polymerase II. PARP1 can function as both a positive and negative regulator of transcription elongation, depending on the context. It positively regulates transcription elongation by mediating poly-ADP-ribosylation of NELFE, inhibiting its RNA-binding activity and alleviating transcription pausing. Conversely, in response to DNA damage, PARP1 negatively regulates transcription elongation by poly-ADP-ribosylating CCNT1, disrupting its phase separation activity and subsequent activation of CDK9. PARP1 interacts with CARM1 and participates in replication fork progression by mediating poly-ADP-ribosylation at replication forks, slowing fork progression. PARP1-generated poly-ADP-ribose chains play a role in poly-ADP-ribose-dependent cell death, a process known as parthanatos. PARP1 negatively regulates the cGAS-STING pathway by mediating poly-ADP-ribosylation of CGAS. Following phosphorylation by PRKDC, PARP1 translocates to the cytosol and inactivates CGAS through poly-ADP-ribosylation. It also acts as a negative regulator of adipogenesis by poly-ADP-ribosylating histone H2B on Glu-35, inhibiting phosphorylation of H2B at Ser-36, and blocking the expression of pro-adipogenetic genes. In collaboration with NMNAT1, PARG, and NUDT5, PARP1 participates in nuclear ATP synthesis, which is essential for energy-intensive chromatin remodeling events. PARP1 promotes AIFM1-mediated apoptosis. Following caspase-3 and caspase-7 cleavage during apoptosis, PARP1 translocates to the cytoplasm, undergoes auto-poly-ADP-ribosylation, and serves as a poly-ADP-ribose carrier to induce AIFM1-mediated apoptosis. This cleaved form irreversibly binds to DNA breaks, interfering with DNA repair and promoting DNA damage-induced apoptosis.

PARP1 is also known as ADPRT, ADPRT 1, ADPRT1, ARTD1, PARP, PARP-1, PARS, PPOL, Poly-PARP, pADPRT-1.

Associated Diseases

WES Whole Exome Sequencing

Clinical Exome Sequencing