Trp53bp1-KO Mouse

Trp53bp1, also known as p53 binding protein 1, is a tumor suppressor that nucleates the anti-end resection machinery at DNA double-strand breaks, countering BRCA1 activity [1]. It is involved in DNA repair pathway choice, regulating the balance between homologous recombination (HR) and non-homologous end joining (NHEJ), which is crucial for maintaining genome integrity [1,2,3,4,5,6].

In cancer research, loss-of-function experiments have provided key insights. In BRCA1-mutant tumors, loss of 53BP1 leads to DNA end processing and HR restoration, causing resistance to PARP inhibitors [1]. In ovarian and pancreatic cancer, 53BP1 loss activates the cGAS-STING pathway due to increased cytoplasmic double-stranded DNA from 'leaky' DNA end resection, enhancing anti-tumor immunity and correlating with a response to immune checkpoint blockade [1]. In somatic cell reprogramming, inactivation of 53bp1 rescues reprogramming in Brca1-deficient cells as it elevates HDR [2]. Also, 53BP1 deficiency leads to hyperrecombination via break-induced replication (BIR), highlighting its role in suppressing genome instability [4].

In conclusion, Trp53bp1 is essential for DNA repair pathway choice and maintaining genome integrity. Its loss-of-function models in cancer research have revealed its significance in tumor immunogenicity, response to cancer therapies like PARP inhibitors and immune checkpoint blockade, as well as in somatic cell reprogramming. Understanding Trp53bp1 provides insights into disease mechanisms and potential therapeutic strategies for malignancies.

References:

1. Sun, Yajie, Patterson-Fortin, Jeffrey, Han, Sen, Konstantinopoulos, Panagiotis A, Chowdhury, Dipanjan. 2024. 53BP1 loss elicits cGAS-STING-dependent antitumor immunity in ovarian and pancreatic cancer. In Nature communications, 15, 6676. doi:10.1038/s41467-024-50999-2. https://pubmed.ncbi.nlm.nih.gov/39107288/

2. Georgieva, Daniela, Wang, Ning, Taglialatela, Angelo, Baer, Richard, Egli, Dieter. 2024. BRCA1 and 53BP1 regulate reprogramming efficiency by mediating DNA repair pathway choice at replication-associated double-strand breaks. In Cell reports, 43, 114006. doi:10.1016/j.celrep.2024.114006. https://pubmed.ncbi.nlm.nih.gov/38554279/

3. King, Ashleigh, Reichl, Pia I, Metson, Jean S, Davies, Benjamin, Chapman, J Ross. 2024. Shieldin and CST co-orchestrate DNA polymerase-dependent tailed-end joining reactions independently of 53BP1-governed repair pathway choice. In Nature structural & molecular biology, 32, 86-97. doi:10.1038/s41594-024-01381-9. https://pubmed.ncbi.nlm.nih.gov/39227718/

4. Shah, Sameer Bikram, Li, Youhang, Li, Shibo, Wang, Hailong, Wu, Xiaohua. 2024. 53BP1 deficiency leads to hyperrecombination using break-induced replication (BIR). In Nature communications, 15, 8648. doi:10.1038/s41467-024-52916-z. https://pubmed.ncbi.nlm.nih.gov/39368985/

5. Mirman, Zachary, Lottersberger, Francisca, Takai, Hiroyuki, Durocher, Daniel, de Lange, Titia. 2018. 53BP1-RIF1-shieldin counteracts DSB resection through CST- and Polα-dependent fill-in. In Nature, 560, 112-116. doi:10.1038/s41586-018-0324-7. https://pubmed.ncbi.nlm.nih.gov/30022158/

6. Xu, Guotai, Chapman, J Ross, Brandsma, Inger, Borst, Piet, Rottenberg, Sven. 2015. REV7 counteracts DNA double-strand break resection and affects PARP inhibition. In Nature, 521, 541-544. doi:10.1038/nature14328. https://pubmed.ncbi.nlm.nih.gov/25799992/