Interplay between ATM and ATR in the regulation of common fragile site stability

E. Ozeri-Galai, M. Schwartz, A. Rahat, B. Kerem*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

Common fragile sites are specific genomic loci that form constrictions and gaps on metaphase chromosomes under conditions that slow, but do not arrest, DNA replication. These sites have been shown to have a role in various chromosomal rearrangements in tumors. Different DNA damage response proteins were shown to regulate fragile site stability, including ataxia-telangiectasia and Rad3-related (ATR) and its effector Chk1. Here, we investigated the role of ataxia-telangiectasia mutated (ATM), the main transducer of DNA double-strand break (DSB) signal, in this regulation. We demonstrate that replication stress conditions, which induce fragile site expression, lead to DNA fragmentation and recruitment of phosphorylated ATM to nuclear foci at DSBs. We further show that ATM plays a role in maintaining fragile site stability, which is revealed only in the absence of ATR. However, the activation of ATM under these replication stress conditions is ATR independent. Following conditions that induce fragile site expression both ATR and ATM phosphorylate Chk1, suggesting that both proteins regulate fragile site expression probably via their effect on Chk1 activation. Our findings provide new insights into the interplay between ATR and ATM pathways in response to partial replication inhibition and in the regulation of fragile site stability.

Original languageAmerican English
Pages (from-to)2109-2117
Number of pages9
JournalOncogene
Volume27
Issue number15
DOIs
StatePublished - 3 Apr 2008

Bibliographical note

Funding Information:
This research was partially supported by grants from the Ministry of Science and Technology Israel, the Deutsches Krebsforschungszetrum (DKFZ) and the Israel Cancer Association through the donation from Linda R Kaminow in honor of Ed Fox to BK

Keywords

  • ATM
  • ATR
  • Chk1
  • Double strand breaks
  • Fragile sites
  • Replication stress

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