hMSH2 recruits ATR to DNA damage sites for activation during DNA damage-induced apoptosis

Navjotsingh Pabla, Zhengwei Ma, Michael A. McIlhatton, Richard Fishel, Zheng Dong

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

DNA damage response (DDR) activates a complex signaling network that triggers DNA repair, cell cycle arrest, and/or cell death. Depending on the type and severity of DNA lesion, DDR is controlled by "master" regulators including ATM and ATR protein kinases. Cisplatin, a major chemotherapy drug that cross-links DNA, induces ATR-dependent DDR, resulting in apoptosis. However, it is unclear how ATR is activated. To identify the key regulators of ATR, we analyzed the proteins that associate with ATR after cisplatin treatment by blue native-PAGE and co-immunoprecipitation. The mismatch repair protein hMSH2 was found to be a major ATR-binding protein. Functionally, ATR activation and its recruitment to nuclear foci during cisplatin treatment were attenuated, and DNA damage signaling, involving Chk2, p53, and PUMA-α, was suppressed in hMSH2-deficient cells. ATR activation induced by the DNA methylating agent N-methyl-N-nitrosourea was also shown to be hMSH2-dependent. Intriguingly, hMSH2-mediated ATR recruitment and activation appeared independent of replication protein A, Rad17, and the Rad9-Hus1-Rad1 protein complex. Together the results support a hMSH2-dependent pathway of ATR activation and downstream Chk2/p53 signaling.

Original languageEnglish (US)
Pages (from-to)10411-10418
Number of pages8
JournalJournal of Biological Chemistry
Volume286
Issue number12
DOIs
StatePublished - Mar 25 2011

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DNA Damage
Chemical activation
Apoptosis
Cisplatin
DNA
Ataxia Telangiectasia Mutated Proteins
Replication Protein A
Native Polyacrylamide Gel Electrophoresis
Methylnitrosourea
Proteins
DNA Mismatch Repair
Cell Cycle Checkpoints
Immunoprecipitation
DNA Repair
Protein Kinases
Carrier Proteins
Repair
Cell Death
Drug Therapy
Chemotherapy

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

hMSH2 recruits ATR to DNA damage sites for activation during DNA damage-induced apoptosis. / Pabla, Navjotsingh; Ma, Zhengwei; McIlhatton, Michael A.; Fishel, Richard; Dong, Zheng.

In: Journal of Biological Chemistry, Vol. 286, No. 12, 25.03.2011, p. 10411-10418.

Research output: Contribution to journalArticle

Pabla, Navjotsingh ; Ma, Zhengwei ; McIlhatton, Michael A. ; Fishel, Richard ; Dong, Zheng. / hMSH2 recruits ATR to DNA damage sites for activation during DNA damage-induced apoptosis. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 12. pp. 10411-10418.
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