Lyn tyrosine kinase promotes silencing of ATM-dependent checkpoint signaling during recovery from DNA double-strand breaks

Yasunori Fukumoto; Kazumasa Kuki; Mariko Morii; Takahito Miura; Takuya Honda; Kenichi Ishibashi; Hitomi Hasegawa; Sho Kubota; Yudai Ide; Noritaka Yamaguchi; Yuji Nakayama; Naoto Yamaguchi

doi:10.1016/j.bbrc.2014.08.113

Lyn tyrosine kinase promotes silencing of ATM-dependent checkpoint signaling during recovery from DNA double-strand breaks

Biochem Biophys Res Commun. 2014 Sep 26;452(3):542-7. doi: 10.1016/j.bbrc.2014.08.113. Epub 2014 Aug 28.

Affiliations

¹ Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan. Electronic address: fukumoto@faculty.chiba-u.jp.
² Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
³ Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan. Electronic address: nyama@faculty.chiba-u.jp.

PMID: 25173936
DOI: 10.1016/j.bbrc.2014.08.113

Abstract

DNA damage activates the DNA damage checkpoint and the DNA repair machinery. After initial activation of DNA damage responses, cells recover to their original states through completion of DNA repair and termination of checkpoint signaling. Currently, little is known about the process by which cells recover from the DNA damage checkpoint, a process called checkpoint recovery. Here, we show that Src family kinases promote inactivation of ataxia telangiectasia mutated (ATM)-dependent checkpoint signaling during recovery from DNA double-strand breaks. Inhibition of Src activity increased ATM-dependent phosphorylation of Chk2 and Kap1. Src inhibition increased ATM signaling both in G2 phase and during asynchronous growth. shRNA knockdown of Lyn increased ATM signaling. Src-dependent nuclear tyrosine phosphorylation suppressed ATM-mediated Kap1 phosphorylation. These results suggest that Src family kinases are involved in upstream signaling that leads to inactivation of the ATM-dependent DNA damage checkpoint.

Keywords: Cell cycle; Checkpoint control; Checkpoint recovery; DNA damage; DNA damage response; Src.

Publication types

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

MeSH terms

Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors
Ataxia Telangiectasia Mutated Proteins / genetics*
Ataxia Telangiectasia Mutated Proteins / metabolism
Cell Cycle Checkpoints / drug effects
Cell Cycle Checkpoints / genetics*
Checkpoint Kinase 2 / genetics
Checkpoint Kinase 2 / metabolism
DNA Breaks, Double-Stranded / drug effects
Doxorubicin / pharmacology
Gene Expression Regulation
HeLa Cells
Histones / genetics
Histones / metabolism
Humans
Phosphorylation
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Repressor Proteins / genetics
Repressor Proteins / metabolism
Signal Transduction / drug effects
Signal Transduction / genetics*
Topoisomerase II Inhibitors / pharmacology
Tripartite Motif-Containing Protein 28
src-Family Kinases / genetics*
src-Family Kinases / metabolism

Substances

H2AX protein, human
Histones
RNA, Small Interfering
Repressor Proteins
Topoisomerase II Inhibitors
Doxorubicin
TRIM28 protein, human
Tripartite Motif-Containing Protein 28
Checkpoint Kinase 2
lyn protein-tyrosine kinase
src-Family Kinases
ATM protein, human
Ataxia Telangiectasia Mutated Proteins
CHEK2 protein, human