Parp1-KO Mouse

Poly(ADP-ribose) polymerase 1 (PARP1), also known as ADPRT1, is a multifunctional human ADP-ribosyltransferase. It plays a key role in multiple DNA repair pathways such as base excision repair (BER), non-homologous end joining (NHEJ), homologous recombination (HR), and Okazaki-fragment processing pathways. In response to DNA strand breaks, PARP1 covalently attaches ADP-ribose moieties to itself and other proteins, recruiting DNA repair proteins to the damage site [2].

PARP1 UFMylation at K548 is required for efficient CHK1 activation during replication stress. Inactivation of UFL1, the E3 enzyme for UFMylation, leads to delayed CHK1 activation similar to PARP1-deficient cells. PARP1 UFMylation-deficient mutant (K548R) and pathogenic mutant (F553L) compromise CHK1 activation, replication fork restart, and chromosome stability. PARP1 UFMylation-deficient knock-in mice are more sensitive to replication stress from anticancer treatments, showing that PARP1 UFMylation promotes replication fork stability and safeguards genome integrity [1].

In conclusion, PARP1 is crucial for DNA repair and maintaining genomic integrity. Model-based research, especially using PARP1 UFMylation-deficient knock-in mice, reveals its role in replication stress response. Understanding PARP1 function has implications for treating cancers and other diseases related to DNA damage and replication stress.

References:

1. Gong, Yamin, Wang, Zhifeng, Zong, Wen, Wang, Zhao-Qi, Xu, Xingzhi. 2024. PARP1 UFMylation ensures the stability of stalled replication forks. In Proceedings of the National Academy of Sciences of the United States of America, 121, e2322520121. doi:10.1073/pnas.2322520121. https://pubmed.ncbi.nlm.nih.gov/38657044/

2. Spiegel, Jacob O, Van Houten, Bennett, Durrant, Jacob D. 2021. PARP1: Structural insights and pharmacological targets for inhibition. In DNA repair, 103, 103125. doi:10.1016/j.dnarep.2021.103125. https://pubmed.ncbi.nlm.nih.gov/33940558/