Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 326 (5960): 1698-1701

Copyright © 2009 by the American Association for the Advancement of Science

The Fanconi Anemia Pathway Promotes Replication-Dependent DNA Interstrand Cross-Link Repair

Puck Knipscheer,1 Markus Räschle,2 Agata Smogorzewska,3,4,* Milica Enoiu,5 The Vinh Ho,6 Orlando D. Schärer,5,6 Stephen J. Elledge,3 Johannes C. Walter1,{dagger}

Abstract: Fanconi anemia is a human cancer predisposition syndrome caused by mutations in 13 Fanc genes. The disorder is characterized by genomic instability and cellular hypersensitivity to chemicals that generate DNA interstrand cross-links (ICLs). A central event in the activation of the Fanconi anemia pathway is the mono-ubiquitylation of the FANCI-FANCD2 complex, but how this complex confers ICL resistance remains enigmatic. Using a cell-free system, we showed that FANCI-FANCD2 is required for replication-coupled ICL repair in S phase. Removal of FANCD2 from extracts inhibits both nucleolytic incisions near the ICL and translesion DNA synthesis past the lesion. Reversal of these defects requires ubiquitylated FANCI-FANCD2. Our results show that multiple steps of the essential S-phase ICL repair mechanism fail when the Fanconi anemia pathway is compromised.

1 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
2 Department of Molecular Cell Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
3 Department of Genetics, Harvard Medical School, and Division of Genetics, Brigham and Women’s Hospital, Boston, MA 02115, USA.
4 Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
5 Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland.
6 Departments of Pharmacological Sciences and Chemistry, Stony Brook University, Stony Brook, NY 11794, USA.

* Present address: Laboratory of Genome Maintenance, The Rockefeller University, New York, NY 10021, USA.

{dagger} To whom correspondence should be addressed. E-mail: johannes_walter{at}

Regulation of FANCD2 and FANCI monoubiquitination by their interaction and by DNA.
S. Longerich, Y. Kwon, M.-S. Tsai, A. S. Hlaing, G. M. Kupfer, and P. Sung (2014)
Nucleic Acids Res.
   Abstract »    Full Text »    PDF »
Damage-dependent regulation of MUS81-EME1 by Fanconi anemia complementation group A protein.
A. Benitez, F. Yuan, S. Nakajima, L. Wei, L. Qian, R. Myers, J. J. Hu, L. Lan, and Y. Zhang (2014)
Nucleic Acids Res. 42, 1671-1683
   Abstract »    Full Text »    PDF »
Why does the bone marrow fail in Fanconi anemia?.
J. I. Garaycoechea and K. J. Patel (2014)
Blood 123, 26-34
   Abstract »    Full Text »    PDF »
Advances in Understanding the Complex Mechanisms of DNA Interstrand Cross-Link Repair.
C. Clauson, O. D. Scharer, and L. Niedernhofer (2013)
Cold Spring Harb Perspect Biol 5, a012732
   Abstract »    Full Text »    PDF »
DNA Damage Response: Three Levels of DNA Repair Regulation.
B. M. Sirbu and D. Cortez (2013)
Cold Spring Harb Perspect Biol 5, a012724
   Abstract »    Full Text »    PDF »
Structure-Specific Endonucleases Xpf and Mus81 Play Overlapping but Essential Roles in DNA Repair by Homologous Recombination.
K. Kikuchi, T. Narita, V. T. Pham, J. Iijima, K. Hirota, I. S. Keka, Mohiuddin, K. Okawa, T. Hori, T. Fukagawa, et al. (2013)
Cancer Res. 73, 4362-4371
   Abstract »    Full Text »    PDF »
Visualizing Inhibition of Nucleosome Mobility and Transcription by Cisplatin-DNA Interstrand Crosslinks in Live Mammalian Cells.
G. Zhu, L. Song, and S. J. Lippard (2013)
Cancer Res. 73, 4451-4460
   Abstract »    Full Text »    PDF »
The Fanconi anemia associated protein FAAP24 uses two substrate specific binding surfaces for DNA recognition.
H. Wienk, J. C. Slootweg, S. Speerstra, R. Kaptein, R. Boelens, and G. E. Folkers (2013)
Nucleic Acids Res. 41, 6739-6749
   Abstract »    Full Text »    PDF »
FANCD2 regulates BLM complex functions independently of FANCI to promote replication fork recovery.
I. Chaudhury, A. Sareen, M. Raghunandan, and A. Sobeck (2013)
Nucleic Acids Res. 41, 6444-6459
   Abstract »    Full Text »    PDF »
Regulation of FANCD2 by the mTOR Pathway Contributes to the Resistance of Cancer Cells to DNA Double-Strand Breaks.
C. Shen, D. Oswald, D. Phelps, H. Cam, C. E. Pelloski, Q. Pang, and P. J. Houghton (2013)
Cancer Res. 73, 3393-3401
   Abstract »    Full Text »    PDF »
The MCM8-MCM9 Complex Promotes RAD51 Recruitment at DNA Damage Sites To Facilitate Homologous Recombination.
J. Park, D. T. Long, K. Y. Lee, T. Abbas, E. Shibata, M. Negishi, Y. Luo, J. C. Schimenti, A. Gambus, J. C. Walter, et al. (2013)
Mol. Cell. Biol. 33, 1632-1644
   Abstract »    Full Text »    PDF »
Defining a genotoxic profile with mouse embryonic stem cells.
T. M. Kim, V. I. Rebel, and P. Hasty (2013)
Experimental Biology and Medicine 238, 285-293
   Abstract »    Full Text »    PDF »
Translesion DNA Synthesis and Mutagenesis in Eukaryotes.
J. E. Sale (2013)
Cold Spring Harb Perspect Biol 5, a012708
   Abstract »    Full Text »    PDF »
Regulation of multiple DNA repair pathways by the Fanconi anemia protein SLX4.
Y. Kim, G. S. Spitz, U. Veturi, F. P. Lach, A. D. Auerbach, and A. Smogorzewska (2013)
Blood 121, 54-63
   Abstract »    Full Text »    PDF »
Human Exonuclease 5 Is a Novel Sliding Exonuclease Required for Genome Stability.
J. L. Sparks, R. Kumar, M. Singh, M. S. Wold, T. K. Pandita, and P. M. Burgers (2012)
J. Biol. Chem. 287, 42773-42783
   Abstract »    Full Text »    PDF »
Repair of cisplatin-induced DNA interstrand crosslinks by a replication-independent pathway involving transcription-coupled repair and translesion synthesis.
M. Enoiu, J. Jiricny, and O. D. Scharer (2012)
Nucleic Acids Res. 40, 8953-8964
   Abstract »    Full Text »    PDF »
Fanconi anemia proteins FANCD2 and FANCI exhibit different DNA damage responses during S-phase.
A. Sareen, I. Chaudhury, N. Adams, and A. Sobeck (2012)
Nucleic Acids Res. 40, 8425-8439
   Abstract »    Full Text »    PDF »
Fanconi proteins get histones moving.
A. J. Deans (2012)
EMBO J. 31, 3511-3512
   Abstract »    Full Text »    PDF »
Histone chaperone activity of Fanconi anemia proteins, FANCD2 and FANCI, is required for DNA crosslink repair.
K. Sato, M. Ishiai, K. Toda, S. Furukoshi, A. Osakabe, H. Tachiwana, Y. Takizawa, W. Kagawa, H. Kitao, N. Dohmae, et al. (2012)
EMBO J. 31, 3524-3536
   Abstract »    Full Text »    PDF »
Epstein-Barr Virus BPLF1 Deubiquitinates PCNA and Attenuates Polymerase {eta} Recruitment to DNA Damage Sites.
C. B. Whitehurst, C. Vaziri, J. Shackelford, and J. S. Pagano (2012)
J. Virol. 86, 8097-8106
   Abstract »    Full Text »    PDF »
Characterization of the Human SNM1A and SNM1B/Apollo DNA Repair Exonucleases.
B. Sengerova, C. K. Allerston, M. Abu, S. Y. Lee, J. Hartley, K. Kiakos, C. J. Schofield, J. A. Hartley, O. Gileadi, and P. J. McHugh (2012)
J. Biol. Chem. 287, 26254-26267
   Abstract »    Full Text »    PDF »
Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway.
H. Kim and A. D. D'Andrea (2012)
Genes & Dev. 26, 1393-1408
   Abstract »    Full Text »    PDF »
Competition, collaboration and coordination - determining how cells bypass DNA damage.
J. E. Sale (2012)
J. Cell Sci. 125, 1633-1643
   Abstract »    Full Text »    PDF »
ATR-ATRIP Kinase Complex Triggers Activation of the Fanconi Anemia DNA Repair Pathway.
T. Shigechi, J. Tomida, K. Sato, M. Kobayashi, J. K. Eykelenboom, F. Pessina, Y. Zhang, E. Uchida, M. Ishiai, N. F. Lowndes, et al. (2012)
Cancer Res. 72, 1149-1156
   Abstract »    Full Text »    PDF »
The RecQ4 Orthologue Hrq1 Is Critical for DNA Interstrand Cross-Link Repair and Genome Stability in Fission Yeast.
L. M. Groocock, J. Prudden, J. J. P. Perry, and M. N. Boddy (2012)
Mol. Cell. Biol. 32, 276-287
   Abstract »    Full Text »    PDF »
Structural Analysis of Human FANCL, the E3 Ligase in the Fanconi Anemia Pathway.
C. Hodson, A. R. Cole, L. P. C. Lewis, J. A. Miles, A. Purkiss, and H. Walden (2011)
J. Biol. Chem. 286, 32628-32637
   Abstract »    Full Text »    PDF »
Structure-dependent bypass of DNA interstrand crosslinks by translesion synthesis polymerases.
T. V. Ho, A. Guainazzi, S. B. Derkunt, M. Enoiu, and O. D. Scharer (2011)
Nucleic Acids Res. 39, 7455-7464
   Abstract »    Full Text »    PDF »
Regulation of the Fanconi anemia pathway by a SUMO-like delivery network.
K. Yang, G.-L. Moldovan, P. Vinciguerra, J. Murai, S. Takeda, and A. D. D'Andrea (2011)
Genes & Dev. 25, 1847-1858
   Abstract »    Full Text »    PDF »
Structure of the FANCI-FANCD2 Complex: Insights into the Fanconi Anemia DNA Repair Pathway.
W. Joo, G. Xu, N. S. Persky, A. Smogorzewska, D. G. Rudge, O. Buzovetsky, S. J. Elledge, and N. P. Pavletich (2011)
Science 333, 312-316
   Abstract »    Full Text »    PDF »
Mechanism of RAD51-Dependent DNA Interstrand Cross-Link Repair.
D. T. Long, M. Raschle, V. Joukov, and J. C. Walter (2011)
Science 333, 84-87
   Abstract »    Full Text »    PDF »
Snm1B/Apollo functions in the Fanconi anemia pathway in response to DNA interstrand crosslinks.
J. M. Mason and J. M. Sekiguchi (2011)
Hum. Mol. Genet. 20, 2549-2559
   Abstract »    Full Text »    PDF »
Patient-derived C-terminal mutation of FANCI causes protein mislocalization and reveals putative EDGE motif function in DNA repair.
L. Colnaghi, M. J. K. Jones, X. M. Cotto-Rios, D. Schindler, H. Hanenberg, and T. T. Huang (2011)
Blood 117, 2247-2256
   Abstract »    Full Text »    PDF »
RAD18-mediated ubiquitination of PCNA activates the Fanconi anemia DNA repair network.
L. Geng, C. J. Huntoon, and L. M. Karnitz (2010)
J. Cell Biol. 191, 249-257
   Abstract »    Full Text »    PDF »
Rad18-mediated Translesion Synthesis of Bulky DNA Adducts Is Coupled to Activation of the Fanconi Anemia DNA Repair Pathway.
I. Y. Song, K. Palle, A. Gurkar, S. Tateishi, G. M. Kupfer, and C. Vaziri (2010)
J. Biol. Chem. 285, 31525-31536
   Abstract »    Full Text »    PDF »
CCAAT/enhancer binding protein delta (C/EBP{delta}, CEBPD)-mediated nuclear import of FANCD2 by IPO4 augments cellular response to DNA damage.
J. Wang, T. R. Sarkar, M. Zhou, S. Sharan, D. A. Ritt, T. D. Veenstra, D. K. Morrison, A.-M. Huang, and E. Sterneck (2010)
PNAS 107, 16131-16136
   Abstract »    Full Text »    PDF »
Multiple DNA Damage Signaling and Repair Pathways Deregulated by Simian Virus 40 Large T Antigen.
S. Boichuk, L. Hu, J. Hein, and O. V. Gjoerup (2010)
J. Virol. 84, 8007-8020
   Abstract »    Full Text »    PDF »
Expanded roles of the Fanconi anemia pathway in preserving genomic stability.
Y. Kee and A. D. D'Andrea (2010)
Genes & Dev. 24, 1680-1694
   Abstract »    Full Text »    PDF »
FAN1 Acts with FANCI-FANCD2 to Promote DNA Interstrand Cross-Link Repair.
T. Liu, G. Ghosal, J. Yuan, J. Chen, and J. Huang (2010)
Science 329, 693-696
   Abstract »    Full Text »    PDF »
Ku70 Corrupts DNA Repair in the Absence of the Fanconi Anemia Pathway.
P. Pace, G. Mosedale, M. R. Hodskinson, I. V. Rosado, M. Sivasubramaniam, and K. J. Patel (2010)
Science 329, 219-223
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882