期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 10, 页码 -出版社
MDPI
DOI: 10.3390/ijms22105112
关键词
poly (ADP-ribose) polymerases 1-3; DNA damage response; PARP-DNA binding; ADP-ribosylation; nucleosome remodelling; histone PARylation factor 1; PARP activation
资金
- BBSRC CASE Studentship
- AstraZeneca
PARP 1-3 are multi-domain enzymes known for catalyzing covalent modification of proteins, DNA, and themselves, with important functions in DNA damage response and nucleosome remodelling. Activation of PARP occurs through DNA binding, and modulation of their activity with PARP inhibitors has shown success in cancer therapies.
Poly (ADP-ribose) polymerases (PARP) 1-3 are well-known multi-domain enzymes, catalysing the covalent modification of proteins, DNA, and themselves. They attach mono- or poly-ADP-ribose to targets using NAD(+) as a substrate. Poly-ADP-ribosylation (PARylation) is central to the important functions of PARP enzymes in the DNA damage response and nucleosome remodelling. Activation of PARP happens through DNA binding via zinc fingers and/or the WGR domain. Modulation of their activity using PARP inhibitors occupying the NAD(+) binding site has proven successful in cancer therapies. For decades, studies set out to elucidate their full-length molecular structure and activation mechanism. In the last five years, significant advances have progressed the structural and functional understanding of PARP1-3, such as understanding allosteric activation via inter-domain contacts, how PARP senses damaged DNA in the crowded nucleus, and the complementary role of histone PARylation factor 1 in modulating the active site of PARP. Here, we review these advances together with the versatility of PARP domains involved in DNA binding, the targets and shape of PARylation and the role of PARPs in nucleosome remodelling.
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