Small RNAs recruit chromatin-modifying enzymes MMSET and Tip60 to reconfigure damaged DNA upon double-strand break and facilitate repair

Qinhong Wang, Michael Goldstein

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

Recent reports have demonstrated that DNA double-strand break (DSB)-induced small RNAs (diRNA) play an important role in the DNA damage response (DDR). However, the molecular mechanism by which diRNAs regulate the DDR remains unclear. Here, we report that Dicer-and Drosha-dependent diRNAs function as guiding molecules to promote the recruitment of the methyltransferase MMSET (WHSC1) and the acetyltransferase Tip60 (KAT5) to the DSB, where local levels of histone H4 di-and tri-methylation at lysine 20 (H4K20me2, 3) and H4 acetylation at lysine 16 (H4K16Ac) were enhanced. These histone modification events resulted in an open, flexible chromatin configuration, as indicated by the increased release of histones γH2AX, H2AX, and H3 from damaged chromatin. Furthermore, we found that diRNA-associated AGO2 interacted with MMSET and Tip60 and that the diRNA binding and catalytic activities of AGO2 were dispensable for the interaction but required for the recruitment of MMSET and Tip60 to DSBs. Consequently, diRNA-mediated chromatin remodeling promoted DSB repair by enhancing the recruitment of Rad51 and BRCA1 to the DSB site. Taken together, our findings reveal an unexpected direct role for diRNAs in regulating chromatin remodeling to facilitate DSB repair, revealing a new layer of DDR regulation involving specialized RNA molecules.

Original languageEnglish
Pages (from-to)1904-1915
Number of pages12
JournalCancer research
Volume76
Issue number7
DOIs
StatePublished - Apr 1 2016

Fingerprint

Dive into the research topics of 'Small RNAs recruit chromatin-modifying enzymes MMSET and Tip60 to reconfigure damaged DNA upon double-strand break and facilitate repair'. Together they form a unique fingerprint.

Cite this