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Review
. 2011 Jun 1;10(11):1757-63.
doi: 10.4161/cc.10.11.15818. Epub 2011 Jun 1.

FANCP/SLX4: a Swiss army knife of DNA interstrand crosslink repair

Kelly E Cybulski  1 , Niall G Howlett
Affiliations
Review

FANCP/SLX4: a Swiss army knife of DNA interstrand crosslink repair

Kelly E Cybulski et al. Cell Cycle. .

Abstract

Fanconi anemia (FA) is a rare genetic disease characterized by congenital abnormalities, bone marrow failure and heightened cancer susceptibility. The FA proteins are known to function in the cellular defense against DNA interstrand crosslinks (ICLs), a process that remains poorly understood. A recent spate of discoveries has led to the identification of one new FA gene, FANCP/SLX4, and two strong candidate FA genes, FAN1 and RAD51C. In this perspective we describe the discovery of FANCP/SLX4 and discuss how these new findings collectively refine our understanding of DNA ICL repair.

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Figures

Figure 1
Figure 1
FANCP/SLX4 functions as a molecular platform for several structure specific endonucleases. Depiction of several known or suspected FANCP/SLX4 protein interactions. Domains typewritten in gray text are evolutionarily diverged and are no longer active. Shaded green boxes indicate the regions of FANCP/SLX4 necessary for interaction with the corresponding heterodimer. The shaded yellow box depicts a speculative interaction between monoubiquitin on K561 of the FANCD2 protein, or a K63-linked ubiquitin chain on an unknown protein, and the UBZ ubiquitin-binding domain of FANCP/SLX4. ARM, Armadillo/beta-catenin-like repeat; BTB/POZ, broad-complex, tramtrack and bric a brac/Poxvirus and zinc finger; CCD, conserved C-terminal domain; DEAH, aspartic acid-glutamic acid-alanine-histidine helicase motif; EDGE, glutamic acid-aspartic acid-glycine-glutamic acid motif; ERCC4, excision repair cross complementation group 4 nuclease domain; HhH, helix-hairpin-helix domain; PHD, plant homeodomain; PIP, PCNA-interacting protein motif; MLR, MEI9XPF-interaction-like region; SAP, SAF-A/B, acinus and PIAS domain; UBZ, ubiquitin-binding zinc finger domain; URI, UvrC-intron-endonuclease domain. Figure adapted from reference .
Figure 2
Figure 2
A speculative model of DNA interstrand crosslink repair. Please see the main text for details. Proteins encoded by bona fide Fanconi anemia (FA) genes are depicted in yellow. Non-FA proteins are depicted in orange. Green arrows depict stages of DNA interstrand crosslink (ICL) repair where the indicated proteins may, or are known to, function. Small red arrows depict sites of endonucleolytic cleavage. The red scissors indicates exonucleolytic DNA strand resection. The ICL is depicted in light blue. De novo DNA synthesis is depicted in navy blue, while newly patched DNA (repair synthesis) is depicted in red. P, phosphate group; Ub, ubiquitin.
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