Prolyl isomerization of FAAP20 catalyzed by PIN1 regulates the Fanconi anemia pathway

PLoS Genetics
Jingming WangHyungjin Kim

Abstract

The Fanconi Anemia (FA) pathway is a multi-step DNA repair process at stalled replication forks in response to DNA interstrand cross-links (ICLs). Pathological mutation of key FA genes leads to the inherited disorder FA, characterized by progressive bone marrow failure and cancer predisposition. The study of FA is of great importance not only to children suffering from FA but also as a model to study cancer pathogenesis in light of genome instability among the general population. FANCD2 monoubiquitination by the FA core complex is an essential gateway that connects upstream DNA damage signaling to enzymatic steps of repair. FAAP20 is a key component of the FA core complex, and regulated proteolysis of FAAP20 mediated by the ubiquitin E3 ligase SCFFBW7 is critical for maintaining the integrity of the FA complex and FA pathway signaling. However, upstream regulatory mechanisms that govern this signaling remain unclear. Here, we show that PIN1, a phosphorylation-specific prolyl isomerase, regulates the integrity of the FA core complex, thus FA pathway activation. We demonstrate that PIN1 catalyzes cis-trans isomerization of the FAAP20 pSer48-Pro49 motif and promotes FAAP20 stability. Mechanistically, PIN1-induced conformational ch...Continue Reading

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Citations

Jan 27, 2020·Environmental and Molecular Mutagenesis·Julie Rageul, Hyungjin Kim
Apr 24, 2020·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Theo Rein
Aug 9, 2020·The Journal of Biological Chemistry·Bhavika NagareddyHyungjin Kim
Jul 22, 2019·DNA Repair·Julie RageulHyungjin Kim

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Methods Mentioned

BETA
ubiquitination
immunoprecipitation
pull-down
NMR
transfection
co-IP
flow cytometry
PCR
electrophoresis

Software Mentioned

Image J
Topspin
ImageJ
CcpNmr
KaleidaGraph
Synergy
GPM X ! Tandem
Prism GraphPad
Attune NxT
MaXQuant Andromeda

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