Skip Navigation


Human Molecular Genetics Advance Access originally published online on January 20, 2005
Human Molecular Genetics 2005 14(5):693-701; doi:10.1093/hmg/ddi065
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
14/5/693    most recent
ddi065v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (47)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Howlett, N. G.
Right arrow Articles by Glover, T. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Howlett, N. G.
Right arrow Articles by Glover, T. W.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Human Molecular Genetics, Vol. 14, No. 5 © Oxford University Press 2005; all rights reserved

The Fanconi anemia pathway is required for the DNA replication stress response and for the regulation of common fragile site stability

Niall G. Howlett1,*, Toshiyasu Taniguchi3,{dagger}, Sandra G. Durkin1, Alan D. D'Andrea3 and Thomas W. Glover1,2

1Department of Human Genetics, 2Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA and 3Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA

* To whom correspondence should be addressed at: Department of Human Genetics, 4909 Buhl, Box 0618, 1241 E. Catherine Street, University of Michigan, Ann Arbor, MI 48109-0618, USA. Tel: +1 7347636169; Fax: +1 7347633784; Email: niallg{at}umich.edu

Received November 12, 2004; Revised January 5, 2005; Accepted January 14, 2005

Fanconi anemia (FA) is a rare multi-genic, autosomal and X-linked recessive disorder characterized by hematological abnormalities, developmental defects and increased cancer susceptibility. Patient-derived FA cells display heightened sensitivity to DNA cross-linking agents such as mitomycin C (MMC). In response to DNA damaging agents, and during S-phase of the cell cycle, the FA pathway is activated via the mono-ubiquitination of FANCD2 (FANCD2-Ub), signaling its translocation to discrete nuclear foci, where it co-localizes with the central DNA repair proteins BRCA1 and RAD51. However, the exact function of activated FANCD2-Ub remains unclear. Here, we have characterized the role of the FA pathway in response to DNA replicative stress by aphidicolin (APH) and hydroxyurea (HU). The FA pathway is strongly activated in response to both agents. In addition, using patient-derived FA cell lines and siRNA targeting FANCD2, we demonstrate a functional requirement for the FA pathway in response to low doses of APH: a replicative stress treatment known to result in chromosome breakage at common fragile sites. Both the total number of chromosome gaps and breaks and breaks at the specific common fragile sites FRA3B and FRA16D were significantly elevated in the absence of an intact FA pathway. Furthermore, we demonstrate that APH activates the mono-ubiquitination of both FANCD2 and PCNA and the phosphorylation of RPA2, signaling processive DNA replication arrest. Following APH treatment, FANCD2-Ub co-localizes with PCNA (early) and RPA2 (late) in discrete nuclear foci. Our results demonstrate an integral role for the FA pathway in the DNA replication stress response.

{dagger} Present address: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
A. N. Suhasini, J. A. Sommers, A. C. Mason, O. N. Voloshin, R. D. Camerini-Otero, M. S. Wold, and R. M. Brosh Jr.
FANCJ Helicase Uniquely Senses Oxidative Base Damage in Either Strand of Duplex DNA and Is Stimulated by Replication Protein A to Unwind the Damaged DNA Substrate in a Strand-specific Manner
J. Biol. Chem., July 3, 2009; 284(27): 18458 - 18470.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
D. Kumari, V. Somma, A. J. Nakamura, W. M. Bonner, E. D'Ambrosio, and K. Usdin
The role of DNA damage response pathways in chromosome fragility in Fragile X syndrome
Nucleic Acids Res., May 21, 2009; (2009) gkp391v1.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
Q. Fan, F. Zhang, B. Barrett, K. Ren, and P. R. Andreassen
A role for monoubiquitinated FANCD2 at telomeres in ALT cells
Nucleic Acids Res., April 1, 2009; 37(6): 1740 - 1754.
[Abstract] [Full Text] [PDF]

Home page
 BMJ Case ReportsHome page
M. Tanwar, R. Kumar, A. Goyal, M. Kumar, T. Dada, G. Singh, R. Sihota, and R. Dada
Rieger syndrome with multiple chromosomal breaks and chromosome 4 deletion
BMJ Case Reports, February 16, 2009; 2009(feb04_1): bcr0620080297 - bcr0620080297.
[Abstract] [Full Text]

Home page
 Cancer Res.Home page
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]

Home page
 JCBHome page
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]

Home page
 Proc. Natl. Acad. Sci. USAHome page
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]

Home page
 J. Virol.Home page
N. Spardy, A. Duensing, D. Charles, N. Haines, T. Nakahara, P. F. Lambert, and S. Duensing
The Human Papillomavirus Type 16 E7 Oncoprotein Activates the Fanconi Anemia (FA) Pathway and Causes Accelerated Chromosomal Instability in FA Cells
J. Virol., December 1, 2007; 81(23): 13265 - 13270.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
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]

Home page
 Clin. Cancer Res.Home page
E. Gallmeier and S. E. Kern
Targeting Fanconi Anemia/BRCA2 Pathway Defects in Cancer: The Significance of Preclinical Pharmacogenomic Models
Clin. Cancer Res., January 1, 2007; 13(1): 4 - 10.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
J. Dunn, M. Potter, A. Rees, and T. M. Runger
Activation of the Fanconi Anemia/BRCA Pathway and Recombination Repair in the Cellular Response to Solar Ultraviolet Light
Cancer Res., December 1, 2006; 66(23): 11140 - 11147.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
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]

Home page
 Molecular Cancer TherapeuticsHome page
Y. Wang, T. Wiltshire, J. Senft, S. L. Wenger, E. Reed, and W. Wang
Fanconi anemia D2 protein confers chemoresistance in response to the anticancer agent, irofulven
Mol. Cancer Ther., December 1, 2006; 5(12): 3153 - 3161.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
E. Barroso, R.L. Milne, L.P. Fernandez, P. Zamora, J.I. Arias, J. Benitez, and G. Ribas
FANCD2 associated with sporadic breast cancer risk
Carcinogenesis, September 1, 2006; 27(9): 1930 - 1937.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
T. Taniguchi and A. D. D'Andrea
Molecular pathogenesis of Fanconi anemia: recent progress
Blood, June 1, 2006; 107(11): 4223 - 4233.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
A. Sobeck, S. Stone, V. Costanzo, B. de Graaf, T. Reuter, J. de Winter, M. Wallisch, Y. Akkari, S. Olson, W. Wang, et al.
Fanconi Anemia Proteins Are Required To Prevent Accumulation of Replication-Associated DNA Double-Strand Breaks
Mol. Cell. Biol., January 15, 2006; 26(2): 425 - 437.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
R. D. Kennedy and A. D. D'Andrea
The Fanconi Anemia/BRCA pathway: new faces in the crowd
Genes & Dev., December 15, 2005; 19(24): 2925 - 2940.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
E. El Achkar, M. Gerbault-Seureau, M. Muleris, B. Dutrillaux, and M. Debatisse
Premature condensation induces breaks at the interface of early and late replicating chromosome bands bearing common fragile sites
PNAS, December 13, 2005; 102(50): 18069 - 18074.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
M. Schwartz, E. Zlotorynski, M. Goldberg, E. Ozeri, A. Rahat, C. l. Sage, B. P.C. Chen, D. J. Chen, R. Agami, and B. Kerem
Homologous recombination and nonhomologous end-joining repair pathways regulate fragile site stability
Genes & Dev., November 15, 2005; 19(22): 2715 - 2726.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
T. W. Glover, M. F. Arlt, A. M. Casper, and S. G. Durkin
Mechanisms of common fragile site instability
Hum. Mol. Genet., October 15, 2005; 14(suppl_2): R197 - R205.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
M. Finnis, S. Dayan, L. Hobson, G. Chenevix-Trench, K. Friend, K. Ried, D. Venter, E. Woollatt, E. Baker, and R. I. Richards
Common chromosomal fragile site FRA16D mutation in cancer cells
Hum. Mol. Genet., May 15, 2005; 14(10): 1341 - 1349.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.