PARP1, poly-(ADP)-ribose polymerase, in the DNA damage response

NCBI ID: G142

PARP1

PARP1, poly-(ADP)-ribose polymerase, in the DNA damage response

It is involved in the repair of oxidative DNA damages and is activated by DNA damage. PARP1 detects DNA damage through its DNA-binding domain (DBD) and synthesizes poly(ADP) ribose (pADPr) on acceptor proteins, leading to the recruitment of repair proteins to the damaged DNA. It is involved in various repair mechanisms, including base excision repair (BER), homologous recombination (HR), and alternative non-homologous end joining (Alt-NHEJ). PARP1 inhibitors prevent the synthesis of pADPr and hinder downstream repair processes, increasing the duration of DNA lesions. The principle of synthetic lethality applies to PARP inhibitors, as they selectively kill tumor cells by inducing DNA damage that cannot be repaired in the absence of a functional HR pathway. PARP inhibition also leads to mitotic catastrophe and DNA replication stress. In summary, PARP1 is a key protein involved in DNA damage response and repair mechanisms, and its inhibition has significant implications for cancer treatment.
PARP1, also known as PARP, plays a crucial role in various biological processes and is associated with different diseases. In breast cancer cells, the combination of PARP inhibitors with zoledronic acid disrupts antiapoptotic and proliferative signaling pathways, leading to hindered cell division. PARP1 is also involved in regulating gene expression and can act as a transcriptional coactivator/co-repressor in the inflammatory process. Moreover, PARP1 activity influences the function of insulators and may be a target for treating EBV infection. In cardiovascular diseases like atrial fibrillation (AF) and atherosclerotic CAD, PARP1 activation and NAD+ depletion contribute to ATP depletion and ROS production, leading to mitochondrial dysfunction. Additionally, PARP1 inhibitors have shown antiviral effects, potentially inhibiting viral replication and modulating inflammation. The wide range of PARP1 targets and its involvement in various diseases suggest that targeting PARP1 could have therapeutic benefits in different contexts .

Protein Name: Poly(ADP-ribose) Polymerase 1

Functions: Poly-ADP-ribosyltransferase that mediates poly-ADP-ribosylation of proteins and plays a key role in DNA repair (PubMed:17177976, PubMed:18172500, PubMed:20388712, PubMed:19344625, PubMed:19661379, PubMed:21680843, PubMed:23230272, PubMed:25043379, PubMed:26344098, PubMed:32028527, PubMed:30104678, PubMed:33186521, PubMed:31796734, PubMed:32358582, PubMed:34737271, PubMed:34465625, PubMed:18055453, PubMed:22582261, PubMed:26626479, PubMed:26626480, PubMed:32241924). Mediates glutamate, aspartate, serine, histidine or tyrosine ADP-ribosylation of proteins: the ADP-D-ribosyl group of NAD(+) is transferred to the acceptor carboxyl group of target residues and further ADP-ribosyl groups are transferred to the 2'-position of the terminal adenosine moiety, building up a polymer with an average chain length of 20-30 units (PubMed:7852410, PubMed:9315851, PubMed:19764761, PubMed:25043379, PubMed:28190768, PubMed:29954836, PubMed:35393539). Serine ADP-ribosylation of proteins constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage (PubMed:33186521, PubMed:34874266). Specificity for the different amino acids is conferred by interacting factors, such as HPF1 and NMNAT1 (PubMed:28190768, PubMed:29954836, PubMed:32028527, PubMed:33186521, PubMed:34874266, PubMed:34625544, PubMed:33589610). Following interaction with HPF1, catalyzes serine ADP-ribosylation of target proteins; HPF1 confers serine specificity by completing the PARP1 active site (PubMed:28190768, PubMed:29954836, PubMed:32028527, PubMed:33186521, PubMed:34874266, PubMed:34625544, PubMed:33589610). Also catalyzes tyrosine ADP-ribosylation of target proteins following interaction with HPF1 (PubMed:30257210, PubMed:29954836). Following interaction with NMNAT1, catalyzes glutamate and aspartate ADP-ribosylation of target proteins; NMNAT1 confers glutamate and aspartate specificity (By similarity). PARP1 initiates the repair of DNA breaks: recognizes and binds DNA breaks within chromatin and recruits HPF1, licensing serine ADP-ribosylation of target proteins, such as histones (H2BS6ADPr and H3S10ADPr), thereby promoting decompaction of chromatin and the recruitment of repair factors leading to the reparation of DNA strand breaks (PubMed:17177976, PubMed:18172500, PubMed:19344625, PubMed:19661379, PubMed:23230272, PubMed:27067600, PubMed:34874266, PubMed:34465625). HPF1 initiates serine ADP-ribosylation but restricts the polymerase activity of PARP1 in order to limit the length of poly-ADP-ribose chains (PubMed:34732825, PubMed:33683197, PubMed:34795260). In addition to base excision repair (BER) pathway, also involved in double-strand breaks (DSBs) repair: together with TIMELESS, accumulates at DNA damage sites and promotes homologous recombination repair by mediating poly-ADP-ribosylation (PubMed:26344098, PubMed:30356214). Mediates the poly-ADP-ribosylation of a number of proteins, including itself, APLF, CHFR and NFAT5 (PubMed:17396150, PubMed:19764761, PubMed:34049076). In addition to proteins, also able to ADP-ribosylate DNA: catalyzes ADP-ribosylation of DNA strand break termini containing terminal phosphates and a 2'-OH group in single- and double-stranded DNA, respectively (PubMed:27471034). Required for PARP9 and DTX3L recruitment to DNA damage sites (PubMed:23230272). PARP1-dependent PARP9-DTX3L-mediated ubiquitination promotes the rapid and specific recruitment of 53BP1/TP53BP1, UIMC1/RAP80, and BRCA1 to DNA damage sites (PubMed:23230272). PARP1-mediated DNA repair in neurons plays a role in sleep: senses DNA damage in neurons and promotes sleep, facilitating efficient DNA repair (By similarity). In addition to DNA repair, also involved in other processes, such as transcription regulation, programmed cell death, membrane repair, adipogenesis and innate immunity (PubMed:17177976, PubMed:19344625, PubMed:15607977, PubMed:27256882, PubMed:32844745, PubMed:32315358, PubMed:35124853, PubMed:35460603, PubMed:35393539). Acts as a repressor of transcription: binds to nucleosomes and modulates chromatin structure in a manner similar to histone H1, thereby altering RNA polymerase II (PubMed:15607977, PubMed:22464733). Acts both as a positive and negative regulator of transcription elongation, depending on the context (PubMed:27256882, PubMed:35393539). Acts as a positive regulator of transcription elongation by mediating poly-ADP-ribosylation of NELFE, preventing RNA-binding activity of NELFE and relieving transcription pausing (PubMed:27256882). Acts as a negative regulator of transcription elongation in response to DNA damage by catalyzing poly-ADP-ribosylation of CCNT1, disrupting the phase separation activity of CCNT1 and subsequent activation of CDK9 (PubMed:35393539). Involved in replication fork progression following interaction with CARM1: mediates poly-ADP-ribosylation at replication forks, slowing fork progression (PubMed:33412112). Poly-ADP-ribose chains generated by PARP1 also play a role in poly-ADP-ribose-dependent ce

The "PARP1 Target / Biomarker Review Report" is a customizable review of hundreds up to thousends of related scientific research literature by AI technology, covering specific information about PARP1 comprehensively, including but not limited to:
•   general information;
•   protein structure and compound binding;
•   protein biological mechanisms;
•   its importance;
•   the target screening and validation;
•   expression level;
•   disease relevance;
•   drug resistance;
•   related combination drugs;
•   pharmacochemistry experiments;
•   related patent analysis;
•   advantages and risks of development, etc.
The report is helpful for project application, drug molecule design, research progress updates, publication of research papers, patent applications, etc. If you are interested to get a full version of this report, please feel free to contact us at BD@silexon.ai

More Common Targets