ATM activation is impaired in human cells defective in RecQL4 helicase activity

Soon-Young Park; Hyunsup Kim; Jun-Sub Im; Joon-Kyu Lee

doi:10.1016/j.bbrc.2018.12.151

ATM activation is impaired in human cells defective in RecQL4 helicase activity

Biochem Biophys Res Commun. 2019 Feb 5;509(2):379-383. doi: 10.1016/j.bbrc.2018.12.151. Epub 2018 Dec 26.

Authors

Soon-Young Park¹, Hyunsup Kim², Jun-Sub Im¹, Joon-Kyu Lee³

Affiliations

¹ Department of Biology Education, Seoul National University, Seoul, 08826, South Korea.
² Interdisciplinary Graduate Program in Genetic Engineering, Seoul National University, Seoul, 08826, South Korea.
³ Department of Biology Education, Seoul National University, Seoul, 08826, South Korea; Interdisciplinary Graduate Program in Genetic Engineering, Seoul National University, Seoul, 08826, South Korea. Electronic address: joonlee@snu.ac.kr.

PMID: 30594395
DOI: 10.1016/j.bbrc.2018.12.151

Abstract

RecQL4 has been shown to be involved in DNA replication and repair, but its role in DNA damage checkpoint pathway has not been reported. Here, we show that RecQL4 plays an important role in the activation of ataxia telangiectasia mutated (ATM)-dependent checkpoint pathway in human cells. Cells depleted with RecQL4 or Rothmund-Thomson syndrome cells showed significant impairment in the activation of ATM and the downstream effector proteins such as checkpoint kinase 2 and p53 after DNA damage. This defect was recovered with the expression of wild type RecQL4 but not any mutant RecQL4 proteins with defective helicase activities. While RecQL4 failed to show any direct interaction with ATM, it stably interacted with the Mre11-Rad50-Nbs1 complex that is essential for the activation of ATM and was localized on the DNA damage foci. Thus, our results suggest that the helicase activity of RecQL4 plays an important role in the activation of ATM-dependent checkpoint pathway against DNA double strand breaks in human cells.

Keywords: ATM; DNA damage checkpoint pathway; DNA double strand break; RecQL4; Rothmund-Thomson syndrome.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acid Anhydride Hydrolases
Ataxia Telangiectasia Mutated Proteins / genetics*
Ataxia Telangiectasia Mutated Proteins / metabolism
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Checkpoint Kinase 2 / genetics
Checkpoint Kinase 2 / metabolism
DNA / genetics*
DNA / metabolism
DNA Breaks, Double-Stranded
DNA Repair Enzymes / genetics
DNA Repair Enzymes / metabolism
DNA Repair*
DNA Replication
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Gene Expression Regulation
Genetic Complementation Test
Humans
MRE11 Homologue Protein / genetics
MRE11 Homologue Protein / metabolism
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Osteoblasts / cytology
Osteoblasts / metabolism
Protein Binding
RecQ Helicases / deficiency
RecQ Helicases / genetics*
Rothmund-Thomson Syndrome / genetics*
Rothmund-Thomson Syndrome / metabolism
Rothmund-Thomson Syndrome / pathology
Signal Transduction
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism

Substances

Cell Cycle Proteins
DNA-Binding Proteins
MRE11 protein, human
NBN protein, human
Nuclear Proteins
Tumor Suppressor Protein p53
DNA
Checkpoint Kinase 2
ATM protein, human
Ataxia Telangiectasia Mutated Proteins
CHEK2 protein, human
MRE11 Homologue Protein
Acid Anhydride Hydrolases
RAD50 protein, human
RECQL4 protein, human
RecQ Helicases
DNA Repair Enzymes