TY - JOUR
T1 - Constitutive role of the Fanconi anemia D2 gene in the replication stress response
AU - Tian, Yanyan
AU - Shen, Xi
AU - Wang, Rui
AU - Klages-Mundt, Naeh L.
AU - Lynn, Erica J.
AU - Martin, Sara K.
AU - Ye, Yin
AU - Gao, Min
AU - Chen, Junjie
AU - Schlacher, Katharina
AU - Li, Lei
N1 - Publisher Copyright:
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2017/12/8
Y1 - 2017/12/8
N2 - In response to DNA cross-linking damage, the Fanconi anemia (FA) core complex activates the FA pathway by monou-biquitinating Fanconi anemia complementation group D2 (FANCD2) for the initiation of the nucleolytic processing of the DNA cross-links and stabilization of stalled replication forks. Given that all the classic FA proteins coordinately monoubiq-uitinate FANCD2, it is unclear why losses of individual classic FA genes yield varying cellular sensitivities to cross-linking damage. To address this question, we generated cellular knockout models of FA core complex components and FANCD2 and found that FANCD2-null mutants display higher levels of spontaneous chromosomal damage and hypersensitivity to replication-blocking lesions than Fanconi anemia complementation group L (FANCL)-null mutants, suggesting that FANCD2 provides a basal level of DNA protection countering endogenous lesions in the absence of monoubiquitination. FANCD2’s ubiquitination-independent function is likely involved in optimized recruitment of nucleolytic activities for the processing and protection of stressed replication forks. Our results reveal that FANCD2 has a ubiquitination-independent role in countering endogenous levels of replication stress, a function that is critical for the maintenance of genomic stability.
AB - In response to DNA cross-linking damage, the Fanconi anemia (FA) core complex activates the FA pathway by monou-biquitinating Fanconi anemia complementation group D2 (FANCD2) for the initiation of the nucleolytic processing of the DNA cross-links and stabilization of stalled replication forks. Given that all the classic FA proteins coordinately monoubiq-uitinate FANCD2, it is unclear why losses of individual classic FA genes yield varying cellular sensitivities to cross-linking damage. To address this question, we generated cellular knockout models of FA core complex components and FANCD2 and found that FANCD2-null mutants display higher levels of spontaneous chromosomal damage and hypersensitivity to replication-blocking lesions than Fanconi anemia complementation group L (FANCL)-null mutants, suggesting that FANCD2 provides a basal level of DNA protection countering endogenous lesions in the absence of monoubiquitination. FANCD2’s ubiquitination-independent function is likely involved in optimized recruitment of nucleolytic activities for the processing and protection of stressed replication forks. Our results reveal that FANCD2 has a ubiquitination-independent role in countering endogenous levels of replication stress, a function that is critical for the maintenance of genomic stability.
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U2 - 10.1074/jbc.M117.814780
DO - 10.1074/jbc.M117.814780
M3 - Article
C2 - 29021208
AN - SCOPUS:85037541719
SN - 0021-9258
VL - 292
SP - 20184
EP - 20195
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 49
ER -