Regulation of Rothmund–Thomson syndrome protein RecQL4 functions in DNA replication by SIRT1-mediated deacetylation

Abstract

NAD dependent histone deacetylase SIRT1 has demonstrated involvement in the regulation of stress responses, cellular metabolism, and cell survival. SIRT1 overexpression has been demonstrated to induce G1 arrest, but its function in the cell cycle remains unclear. Here, we identified RecQL4 as a SIRT1 interacting protein through complex purification. RecQL4 is a member of the RecQ DNA helicase family involved in DNA replication, recombination, and repair. Mutations in the RECQL4 gene are responsible for Rothmund–Thomson syndrome (RTS), a severe autosomal recessive disorder causing premature aging and predisposition to cancers. RecQL4 can be acetylated by CBP at lysine 88. Transfection of wild-type RecQL4 into cells derived from an RTS patient can rescue cell proliferation, while a RecQL4 acetylation mutant severely impairs this function. We demonstrated that the acetylation of RecQL4 can regulate both DNA replication activity and the timing of replication firing by dynamically regulating its nuclear localization during the S phase. SIRT1 deacetylates RecQL4 both in vitro and vivo. The acetylation status of RecQL4 affects its loading to the chromatin during the S phase of the cell cycle, consequently affecting DNA replication initiation. Our findings provided new insights on the role of protein acetylation in regulating DNA replication initiation.

Funding

National Institutes of Health(AG026534); National Natural Science Foundation of China(81471405); National Basic Research Program of China (973 Program)(2013CB530801)