TY - JOUR
T1 - DNA requirement in FANCD2 deubiquitination by USP1-UAF1-RAD51AP1 in the Fanconi anemia DNA damage response
AU - Liang, Fengshan
AU - Miller, Adam S.
AU - Longerich, Simonne
AU - Tang, Caroline
AU - Maranon, David
AU - Williamson, Elizabeth A.
AU - Hromas, Robert
AU - Wiese, Claudia
AU - Kupfer, Gary M.
AU - Sung, Patrick
N1 - Funding Information:
We thank Andrew Deans for providing the multi-bacmid for expressing the BL100 complex. This work was supported by CPRIT REI Award RR180029 and US National Institutes of Health grants R01 CA168635, U54 DK106857, R01 CA220123, R01 CA205224, R01 ES007061, R01 GM109645, P01 CA092584, and P30 CA054174. P.S. is the holder of the Robert A. Welch Distinguished Chair in Chemistry (AQ-0012).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Fanconi anemia (FA) is a multigenic disease of bone marrow failure and cancer susceptibility stemming from a failure to remove DNA crosslinks and other chromosomal lesions. Within the FA DNA damage response pathway, DNA-dependent monoubiquitinaton of FANCD2 licenses downstream events, while timely FANCD2 deubiquitination serves to extinguish the response. Here, we show with reconstituted biochemical systems, which we developed, that efficient FANCD2 deubiquitination by the USP1-UAF1 complex is dependent on DNA and DNA binding by UAF1. Surprisingly, we find that the DNA binding activity of the UAF1-associated protein RAD51AP1 can substitute for that of UAF1 in FANCD2 deubiquitination in our biochemical system. We also reveal the importance of DNA binding by UAF1 and RAD51AP1 in FANCD2 deubiquitination in the cellular setting. Our results provide insights into a key step in the FA pathway and help define the multifaceted role of the USP1-UAF1-RAD51AP1 complex in DNA damage tolerance and genome repair.
AB - Fanconi anemia (FA) is a multigenic disease of bone marrow failure and cancer susceptibility stemming from a failure to remove DNA crosslinks and other chromosomal lesions. Within the FA DNA damage response pathway, DNA-dependent monoubiquitinaton of FANCD2 licenses downstream events, while timely FANCD2 deubiquitination serves to extinguish the response. Here, we show with reconstituted biochemical systems, which we developed, that efficient FANCD2 deubiquitination by the USP1-UAF1 complex is dependent on DNA and DNA binding by UAF1. Surprisingly, we find that the DNA binding activity of the UAF1-associated protein RAD51AP1 can substitute for that of UAF1 in FANCD2 deubiquitination in our biochemical system. We also reveal the importance of DNA binding by UAF1 and RAD51AP1 in FANCD2 deubiquitination in the cellular setting. Our results provide insights into a key step in the FA pathway and help define the multifaceted role of the USP1-UAF1-RAD51AP1 complex in DNA damage tolerance and genome repair.
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U2 - 10.1038/s41467-019-10408-5
DO - 10.1038/s41467-019-10408-5
M3 - Article
C2 - 31253762
AN - SCOPUS:85068163694
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2849
ER -