This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: When DNA is damaged, cellular processes respond and repair the DNA. Inhibiting DNA damage repair can be therapeutically beneficial in cancers with genetic vulnerabilities related to DNA damage response.
Jude Children's Research Hospital have uncovered a mechanism behind how this process works, which may have implications for cancer treatment. The results were published today in Molecular Cell. One of the "first responders" to begin DNA damage repair is the enzyme poly(ADP-ribose) polymerase (PARP1).
PARP1 has two known primary functions: to sense DNA damage and send a signal through protein poly(ADP-ribosyl)ation that initiates DNA repair inside a cell. However, how PARP1 overcomes the nucleosome barrier to begin DNA repair was unknown. Using a combination of biochemical and cellular testing, researchers at St.
Jude dissected a direct function of PARP1 in chromatin remodeling for the first time. "Our study revealed a third, previously undescribed role of PARP1 in DNA damage repair, where we observed that the enzyme disassembles the nucleosome to facilitate chromatin accessibility so other downstream repair mechanisms can come in to do their job," said corresponding author Hai Dao, Ph.D., St. Jude Department of Chemical Biology & Therapeutics assistant member.
"But, to our surprise, we observed that PARP1 disassembles the nucleosome in a unique way." The nucleosome, which is the repeating structural unit of chromatin that compacts DNA to fit inside a cell's nucleus, consists of DNA wrapped around a symmetric core of eight histone proteins. Using biochemical and cellular tests, the researchers found that PARP1 asymmetrically evicts two histone proteins next to the site of DNA damage. This in turn leads to the formation of a hexasome (a nucleosomal structure that uses six histone proteins instead of eight).
This mechanism partially opens the nucleosome, and the modified hexasome then serves as a bifunctional hub for recruiting proteins to the site of DNA damage to facilitate repair. A related and surprising finding was revealed when the team observed that a part of histone H2A, called the C-terminal tail—a component of the nucleosome that can contain cancer-associated mutations—molecularly controls PARP1-mediated nucleosome disassembly. The investigators showed that removal of the H2A tail increases sensitivity to DNA-damaging therapies, raising the possibility that the remodeling activity itself could contribute to disease formation.
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