Dnase2a-KO Mouse

Dnase2a, also known as DNase II-alpha, is a lysosomal nuclease. Its primary function is to degrade DNA. It is involved in pathways such as the autophagosome-lysosomal pathway for DNA clearance and is crucial for several biological processes. Genetic models like Dnase2a knockout (KO) mice are valuable for studying its functions [2,3,4,5,6].

In Dnase2a KO mice, undegraded DNA accumulates in both phagocytic and nonphagocytic cells. In nonphagocytic cells, the excess DNA is from damaged nuclear DNA, and its removal requires nuclear export and autophagy-mediated delivery to lysosomes. This accumulated DNA can induce inflammation via the Sting cytosolic DNA-sensing pathway [2]. In atherosclerosis regression, silencing macrophage Dnase2a blocks efferocyte proliferation, apoptotic cell clearance, and plaque stabilization [1]. Dnase2a KO mice also suffer from severe anemia, as it is critical in definitive erythropoiesis where it digests the DNA of extruded nuclei of red blood cells during maturation [4].

In conclusion, Dnase2a is essential for DNA degradation in multiple cellular processes. Studies using Dnase2a KO mouse models have revealed its significance in conditions like inflammation, atherosclerosis, and anemia, highlighting its potential as a target for understanding and treating related diseases.

References:

1. Gerlach, Brennan D, Ampomah, Patrick B, Yurdagul, Arif, Tao, Wei, Tabas, Ira. 2021. Efferocytosis induces macrophage proliferation to help resolve tissue injury. In Cell metabolism, 33, 2445-2463.e8. doi:10.1016/j.cmet.2021.10.015. https://pubmed.ncbi.nlm.nih.gov/34784501/

2. Lan, Yuk Yuen, Londoño, Diana, Bouley, Richard, Rooney, Michael S, Hacohen, Nir. 2014. Dnase2a deficiency uncovers lysosomal clearance of damaged nuclear DNA via autophagy. In Cell reports, 9, 180-192. doi:10.1016/j.celrep.2014.08.074. https://pubmed.ncbi.nlm.nih.gov/25284779/

3. Lan, Yuk Yuen, Heather, James M, Eisenhaure, Thomas, Raychowdhury, Raktima, Hacohen, Nir. 2019. Extranuclear DNA accumulates in aged cells and contributes to senescence and inflammation. In Aging cell, 18, e12901. doi:10.1111/acel.12901. https://pubmed.ncbi.nlm.nih.gov/30706626/

4. Porcu, Susanna, Manchinu, Maria F, Marongiu, Maria F, Grosveld, Frank, Ristaldi, Maria S. 2011. Klf1 affects DNase II-alpha expression in the central macrophage of a fetal liver erythroblastic island: a non-cell-autonomous role in definitive erythropoiesis. In Molecular and cellular biology, 31, 4144-54. doi:10.1128/MCB.05532-11. https://pubmed.ncbi.nlm.nih.gov/21807894/

5. Okabe, Yasutaka, Sano, Teruyuki, Nagata, Shigekazu. 2009. Regulation of the innate immune response by threonine-phosphatase of Eyes absent. In Nature, 460, 520-4. doi:10.1038/nature08138. https://pubmed.ncbi.nlm.nih.gov/19561593/

6. Oka, Takafumi, Hikoso, Shungo, Yamaguchi, Osamu, Komuro, Issei, Otsu, Kinya. . Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. In Nature, 485, 251-5. doi:10.1038/nature10992. https://pubmed.ncbi.nlm.nih.gov/22535248/