Exo1, short for Exonuclease 1, is an evolutionarily conserved 5'-3' exonuclease. It plays a vital role in multiple genomic DNA metabolic pathways such as replication stress response, double strand break repair, mismatch repair, nucleotide excision repair, and telomere maintenance [1,4,7]. These pathways are crucial for maintaining genomic stability, and Exo1's activity is tightly regulated to prevent excessive nucleolytic activity that could lead to genome instability [1].

In prostate cancer, EXO1 promotes tumor progression by regulating lipid metabolism reprogramming via the P53/SREBP1 axis [2]. In BRCA1-deficient cells, EXO1 is essential for protecting against toxic DNA lesions, as its deficiency leads to the accumulation of unresolved double-strand breaks and genomic instability. BRCA1-mutated tumors show elevated EXO1 expression [3,6]. Additionally, in the context of formaldehyde-induced DNA lesions, EXO1 knockout cell lines exhibit sensitivity, with the protein being recruited to chromatin to protect DNA replication forks after formaldehyde exposure [5].

In conclusion, Exo1 is a multi-functional nuclease essential for DNA metabolic pathways and genomic stability. Its role in diseases like prostate cancer and its significance in BRCA1-deficient tumors, as revealed by knockout-based studies, offer potential therapeutic targets. Understanding Exo1's functions can provide insights into disease mechanisms and new strategies for treatment.

References:

1. Sertic, Sarah, Quadri, Roberto, Lazzaro, Federico, Muzi-Falconi, Marco. . EXO1: A tightly regulated nuclease. In DNA repair, 93, 102929. doi:10.1016/j.dnarep.2020.102929. https://pubmed.ncbi.nlm.nih.gov/33087266/

2. Wang, Zefeng, Chao, Zheng, Wang, Qi, Ning, Jinzhuo, Cheng, Fan. 2024. EXO1/P53/SREBP1 axis-regulated lipid metabolism promotes prostate cancer progression. In Journal of translational medicine, 22, 104. doi:10.1186/s12967-023-04822-z. https://pubmed.ncbi.nlm.nih.gov/38279172/

3. van de Kooij, Bert, Schreuder, Anne, Pavani, Raphael, van Attikum, Haico, Noordermeer, Sylvie M. 2024. EXO1 protects BRCA1-deficient cells against toxic DNA lesions. In Molecular cell, 84, 659-674.e7. doi:10.1016/j.molcel.2023.12.039. https://pubmed.ncbi.nlm.nih.gov/38266640/

4. Tran, Phuoc T, Erdeniz, Naz, Symington, Lorraine S, Liskay, R Michael. . EXO1-A multi-tasking eukaryotic nuclease. In DNA repair, 3, 1549-59. doi:. https://pubmed.ncbi.nlm.nih.gov/15474417/

5. Gao, Yuandi, Guitton-Sert, Laure, Dessapt, Julien, Fradet-Turcotte, Amélie, Masson, Jean-Yves. 2023. A CRISPR-Cas9 screen identifies EXO1 as a formaldehyde resistance gene. In Nature communications, 14, 381. doi:10.1038/s41467-023-35802-y. https://pubmed.ncbi.nlm.nih.gov/36693839/

6. van de Kooij, B, Schreuder, A, Pavani, R S, van Attikum, H, Noordermeer, S M. 2023. EXO1-mediated DNA repair by single-strand annealing is essential for BRCA1-deficient cells. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.02.24.529205. https://pubmed.ncbi.nlm.nih.gov/37720033/

7. Keijzers, Guido, Bakula, Daniela, Petr, Michael Angelo, Osborne, Brenna, Scheibye-Knudsen, Morten. 2018. Human Exonuclease 1 (EXO1) Regulatory Functions in DNA Replication with Putative Roles in Cancer. In International journal of molecular sciences, 20, . doi:10.3390/ijms20010074. https://pubmed.ncbi.nlm.nih.gov/30585186/