NDLI: KIAA1018/FAN1 nuclease protects cells against genomic instability induced by interstrand cross-linking agents

Content Provider	PubMed Central
Author	Yoshikiyo, Kazunori Kratz, Katja Hirota, Kouji Nishihara, Kana Takata, Minoru Hitoshi, Kurumizaka Horimoto, Satoshi Takeda, Shunichi Josef, Jiricny
Abstract	Fanconi anemia (FA) is a rare genetic disease characterized by congenital defects, bone marrow failure, chromosomal instability, and cancer susceptibility. One hallmark of cells from FA patients is hypersensitivity to interstrand cross-linking agents, such as the chemotherapeutics cisplatin and mitomycin C (MMC). We have recently characterized a FANCD2/FANCI-associated nuclease, KIAA1018/FAN1, the depletion of which sensitizes human cells to these agents. However, as the down-regulation of FAN1 in human cells was mediated by siRNA and thus only transient, we were unable to study the long-term effects of FAN1 loss on chromosomal stability. We now describe the generation of chicken DT40 B cells, in which the FAN1 locus was disrupted by gene targeting. FAN1-null cells are highly sensitive to cisplatin and MMC, but not to ionizing or UV radiation, methyl methanesulfonate, or camptothecin. The cells do not display elevated sister chromatid exchange frequencies, either sporadic or MMC-induced. Interestingly, MMC treatment causes chromosomal instability that is quantitatively, but not qualitatively, comparable to that seen in FA cells. This finding, coupled with evidence showing that DT40 cells deficient in both FAN1 and FANCC, or FAN1 and FANCJ, exhibited increased sensitivity to cisplatin compared with cells lacking only FAN1, suggests that, despite its association with FANCD2/FANCI, FAN1 in DT40 cells participates in the processing of damage induced by interstrand cross-linking-generating agents also independently of the classical FA pathway.
Related Links	http://dx.doi.org/10.1073/pnas.1011081107
Ending Page	21557
Page Count	5
Starting Page	21553
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	50
Volume Number	107
Language	English
Publisher	National Academy of Sciences
Publisher Date	2010-12-14
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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