Symmetrical dimethylation of H4R3: A bridge linking DNA damage and repair upon oxidative stress

Abstract

The DNA lesions caused by oxidative damage are principally repaired by the base excision repair (BER) pathway. 8-oxoguanine DNA glycosylase 1 (OGG1) initiates BER through recognizing and cleaving the oxidatively damaged nucleobase 8-oxo-7,8-dihydroguanine (8-oxoG). How the BER machinery detects and accesses lesions within the context of chromatin is largely unknown. Here, we found that the symmetrical dimethylarginine of histone H4 (producing H4R3me2s) serves as a bridge between DNA damage and subsequent repair. Intracellular H4R3me2s was significantly increased after treatment with the DNA oxidant reagent H 2 O 2 , and this increase was regulated by OGG1, which could directly interact with the specific arginine methyltransferase, PRMT5. Arginine-methylated H4R3 could associate with flap endonuclease 1 (FEN1) and enhance its nuclease activity and BER efficiency. Furthermore, cells with a decreased level of H4R3me2s were more susceptible to DNA-damaging agents and accumulated more DNA damage lesions in their genome. Taken together, these results demonstrate that H4R3me2s can be recognized as a reader protein that senses DNA damage and a writer protein that promotes DNA repair.

PRMT5 regulates ATF4 transcript splicing and oxidative stress response

“…In keeping with the antioxidative function of PRMT5, knockdown of PRMT5 in ovarian cancer cells increased levels of ROS [ 63 ]. Oxidative stress has also been reported to lead to PRMT5-mediated increase in H4R3 symmetric dimethylation and the base excision repair complex assembly that ensured oxidative DNA lesion repair [ 64 ]. However, a study in renal cells subjected to ischemia-reperfusion stress found that inhibition of PRMT5 ameliorated pyroptosis and oxidative stress [ 65 ] and glutathionylation was found to decrease PRMT5 activity [ 66 ].…”

PRMT5 regulates ATF4 transcript splicing and oxidative stress response

“…In keeping with the antioxidative function of PRMT5, knockdown of PRMT5 in ovarian cancer cells increased levels of ROS (57). Oxidative stress has also been reported to lead to PRMT5-mediated increase in H4R3 symmetric dimethylation and the base excision repair complex assembly that ensured oxidative DNA lesion repair (58). However, a study in renal cells subjected to ischemia-reperfusion stress found that inhibition of PRMT5 ameliorated pyrroptosis and oxidative stress (59) and glutathionylation was found to decrease PRMT5 activity (60).…”

A Bibliometric Analysis of Researches on Flap Endonuclease 1 From 2005 to 2019

“…(25)(26)(27). Base excision repair (BER) is the main method to repair DNA damage caused by oxidative stress (28). The function of FEN1 in long-patch base excision repair appears to be particularly important in the repair of damage caused by oxidative stress.…”