Hpf1-KO Mouse

Hpf1, also known as histone poly(ADP-ribosylation) factor 1, is a crucial co-factor that regulates the activity of poly(ADP-ribose) polymerase 1 (PARP1) and PARP2 [1,2,4,5,6]. It plays a key role in the ADP-ribosylation process, particularly facilitating serine ADP-ribosylation of proteins, mainly PARP1 and histones near DNA breaks. This process is involved in DNA repair pathways, chromatin relaxation, and the recruitment of repair factors, thus being of great biological importance in maintaining genomic stability [1,2,3,7].

In HPF1-deficient cells, the impact on DNA single-strand break repair (SSBR) was investigated. HPF1 loss did not generally increase cellular sensitivity to agents inducing DNA single-strand breaks repaired by PARP1, and SSBR kinetics were largely unaffected. However, HPF1 deficiency partially influenced the accumulation of SSB intermediates after exposure to specific genotoxins in certain cell lines, likely due to altered ADP-ribosylation of chromatin [3]. Also, in LIG1-deficient extracts, depletion of PARP1 or HPF1 resulted in a failure to recruit LIG3 onto chromatin and a subsequent failure in Okazaki fragment joining, suggesting HPF1-dependent PARP activation promotes LIG3-XRCC1-mediated backup pathway of Okazaki fragment ligation [7].

In conclusion, Hpf1 is essential for regulating ADP-ribosylation signaling and chromatin conformation during the DNA damage response. Model-based research, especially studies on HPF1-deficient cells, has revealed its role in DNA repair processes such as SSBR and Okazaki fragment ligation, highlighting its importance in maintaining genomic stability and potentially providing insights into related disease mechanisms [3,7].

References:

1. Smith, Rebecca, Zentout, Siham, Rother, Magdalena, Timinszky, Gyula, Huet, Sébastien. 2023. HPF1-dependent histone ADP-ribosylation triggers chromatin relaxation to promote the recruitment of repair factors at sites of DNA damage. In Nature structural & molecular biology, 30, 678-691. doi:10.1038/s41594-023-00977-x. https://pubmed.ncbi.nlm.nih.gov/37106138/

2. Langelier, Marie-France, Billur, Ramya, Sverzhinsky, Aleksandr, Black, Ben E, Pascal, John M. 2021. HPF1 dynamically controls the PARP1/2 balance between initiating and elongating ADP-ribose modifications. In Nature communications, 12, 6675. doi:10.1038/s41467-021-27043-8. https://pubmed.ncbi.nlm.nih.gov/34795260/

3. Hrychova, Kristyna, Burdova, Kamila, Polackova, Zuzana, Caldecott, Keith W, Hanzlikova, Hana. . Dispensability of HPF1 for cellular removal of DNA single-strand breaks. In Nucleic acids research, 52, 10986-10998. doi:10.1093/nar/gkae708. https://pubmed.ncbi.nlm.nih.gov/39162207/

4. Sun, Fa-Hui, Zhao, Peng, Zhang, Nan, Wong, Catherine C L, Yun, Cai-Hong. 2021. HPF1 remodels the active site of PARP1 to enable the serine ADP-ribosylation of histones. In Nature communications, 12, 1028. doi:10.1038/s41467-021-21302-4. https://pubmed.ncbi.nlm.nih.gov/33589610/

5. Rudolph, Johannes, Roberts, Genevieve, Muthurajan, Uma M, Luger, Karolin. 2021. HPF1 and nucleosomes mediate a dramatic switch in activity of PARP1 from polymerase to hydrolase. In eLife, 10, . doi:10.7554/eLife.65773. https://pubmed.ncbi.nlm.nih.gov/33683197/

6. Suskiewicz, Marcin J, Zobel, Florian, Ogden, Tom E H, Neuhaus, David, Ahel, Ivan. 2020. HPF1 completes the PARP active site for DNA damage-induced ADP-ribosylation. In Nature, 579, 598-602. doi:10.1038/s41586-020-2013-6. https://pubmed.ncbi.nlm.nih.gov/32028527/

7. Kumamoto, Soichiro, Nishiyama, Atsuya, Chiba, Yoshie, Azuma, Yoshiaki, Nakanishi, Makoto. . HPF1-dependent PARP activation promotes LIG3-XRCC1-mediated backup pathway of Okazaki fragment ligation. In Nucleic acids research, 49, 5003-5016. doi:10.1093/nar/gkab269. https://pubmed.ncbi.nlm.nih.gov/33872376/