QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Research Data Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schwartz, M. Articles by Kerem, B. Search for Related Content PubMed PubMed Citation Articles by Schwartz, M. Articles by Kerem, B. Social Bookmarking                   What's this?

RESEARCH PAPER

Homologous recombination and nonhomologous end-joining repair pathways regulate fragile site stability

¹ Department of Genetics, The Life Sciences Institute, The Hebrew University, Jerusalem, Israel 91904; ² Division of Tumor Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; ³ Department of Radiation Oncology, University of Texas Southwestern Medical Center at Dallas, Dallas 75390, Texas; USA

Common fragile sites are specific loci that form gaps and constrictions on metaphase chromosomes exposed to replication stress, which slows DNA replication. These sites have a role in chromosomal rearrangements in tumors; however, the molecular mechanism of their expression is unclear. Here we show that replication stress leads to focus formation of Rad51 and phosphorylated DNA-PKcs, key components of the homologous recombination (HR) and nonhomologous end-joining (NHEJ), double-strand break (DSB) repair pathways, respectively. Down-regulation of Rad51, DNA-PKcs, or Ligase IV, an additional component of the NHEJ repair pathway, leads to a significant increase in fragile site expression under replication stress. Replication stress also results in focus formation of the DSB markers, MDC1 and H2AX. These foci colocalized with those of Rad51 and phospho-DNA-PKcs. Furthermore, H2AX and phospho-DNA-PKcs foci were localized at expressed fragile sites on metaphase chromosomes. These findings suggest that DSBs are formed at common fragile sites as a result of replication perturbation. The repair of these breaks by both HR and NHEJ pathways is essential for chromosomal stability at these sites.

[Keywords: Common fragile sites; double-strand breaks; homologous recombination; nonhomologous end-joining; replication stress; genomic instability]

Received February 16, 2005; revised version accepted September 12, 2005.

Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.340905.

⁴ Corresponding author.

E-MAIL kerem{at}cc.huji.ac.il; FAX 972-2-6584810.

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. Derijck, G. van der Heijden, M. Giele, M. Philippens, and P. de Boer DNA double-strand break repair in parental chromatin of mouse zygotes, the first cell cycle as an origin of de novo mutation Hum. Mol. Genet., July 1, 2008; 17(13): 1922 - 1937. [Abstract] [Full Text] [PDF]

				H. Ishii, K. Mimori, K. Ishikawa, H. Okumura, F. Pichiorri, T. Druck, H. Inoue, A. Vecchione, T. Saito, M. Mori, et al. Fhit-Deficient Hematopoietic Stem Cells Survive Hydroquinone Exposure Carrying Precancerous Changes Cancer Res., May 15, 2008; 68(10): 3662 - 3670. [Abstract] [Full Text] [PDF]

				L. M. Pirzio, P. Pichierri, M. Bignami, and A. Franchitto Werner syndrome helicase activity is essential in maintaining fragile site stability J. Cell Biol., January 28, 2008; 180(2): 305 - 314. [Abstract] [Full Text] [PDF]

				S. G. Durkin, R. L. Ragland, M. F. Arlt, J. G. Mulle, S. T. Warren, and T. W. Glover Replication stress induces tumor-like microdeletions in FHIT/FRA3B PNAS, January 8, 2008; 105(1): 246 - 251. [Abstract] [Full Text] [PDF]

				A. Marusyk, L. J. Wheeler, C. K. Mathews, and J. DeGregori p53 Mediates Senescence-Like Arrest Induced by Chronic Replicational Stress Mol. Cell. Biol., August 1, 2007; 27(15): 5336 - 5351. [Abstract] [Full Text] [PDF]

				K. Debacker, B. Winnepenninckx, N. Ben-Porat, D. FitzPatrick, R. Van Luijk, S. Scheers, B. Kerem, and R Frank Kooy FRA18C: a new aphidicolin-inducible fragile site on chromosome 18q22, possibly associated with in vivo chromosome breakage J. Med. Genet., May 1, 2007; 44(5): 347 - 352. [Abstract] [Full Text] [PDF]

				H. Ishii, K. Mimori, H. Inoue, T. Inageta, K. Ishikawa, S. Semba, T. Druck, F. Trapasso, K. Tani, A. Vecchione, et al. Fhit Modulates the DNA Damage Checkpoint Response Cancer Res., December 1, 2006; 66(23): 11287 - 11292. [Abstract] [Full Text] [PDF]

				R. Bruggmann, A. K. Bharti, H. Gundlach, J. Lai, S. Young, A. C. Pontaroli, F. Wei, G. Haberer, G. Fuks, C. Du, et al. Uneven chromosome contraction and expansion in the maize genome Genome Res., October 1, 2006; 16(10): 1241 - 1251. [Abstract] [Full Text] [PDF]