Studies on the role of RecQL4 in cellular response to DNA damages in human cells

Abstract

Rothmund-Thomson Syndrome (RTS) is an autosomal recessive disorder related with mutation in huRecQL4 gene, which is a member of the RecQ helicase family. The clinical features of RTS are genome instability, growth deficiency, skeletal defects, signs of premature aging, and increased risk of osteosarcoma. It is well established that RecQL4 is involved in DNA replication initiation. However, the role of RecQL4 in cellular response to DNA Double strand breaks (DSBs) is less clear. In this study, I showed that RecQL4 regulates Homologous Recombination (HR) repair by mediating the stability of MRE11-Rad50-Nbs1 (MRN) complex which is primary sensor for DNA DSBs. Depletion of RecQL4 reduced the protein level of MRN complex and downstream signaling pathway involving ATM activation and HR. MRN complex is ubiquitinated by Skp2 E3 ligase and degraded in proteasome. Also, MRN complex interacts with USP28, deubiquitinating enzyme by the assistance of RecQL4. Thus, USP28 deubiquitinates MRN complex and protects from degradation until finishing the HR completely. The helicase activity of RecQL4 is required for the stability of MRN complex and HR repair. Finally, MRN complex is prematurely degraded in RTS fibroblast. These results suggest that RecQL4 might be a key factor plays a critical role in the DNA repair mechanism as well as maintenance of genome integrity in the cell.