Oncotarget

Research Papers:

FANCJ protein is important for the stability of FANCD2/FANCI proteins and protects them from proteasome and caspase-3 dependent degradation

David W. Clark, Kaushlendra Tripathi, Josephine C. Dorsman and Komaraiah Palle _

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Oncotarget. 2015; 6:28816-28832. https://doi.org/10.18632/oncotarget.5006

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Abstract

David W. Clark1, Kaushlendra Tripathi1, Josephine C. Dorsman2, Komaraiah Palle1

1Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA

2Department of Clinical Genetics, Section Oncogenetics, VU University Medical Center, Amsterdam, The Netherlands

Correspondence to:

Komaraiah Palle, e-mail: kpalle@health.southalabama.edu

Keywords: Fanconi anemia, FANCJ, FANCD2, caspase-3, proteasome

Received: June 17, 2015     Accepted: August 11, 2015     Published: August 21, 2015

ABSTRACT

Fanconi anemia (FA) is a rare genome instability syndrome with progressive bone marrow failure and cancer susceptibility. FANCJ is one of 17 genes mutated in FA-patients, comprises a DNA helicase that is vital for properly maintaining genomic stability and is known to function in the FA-BRCA DNA repair pathway. While exact role(s) of FANCJ in this repair process is yet to be determined, it is known to interact with primary effector FANCD2. However, FANCJ is not required for FANCD2 activation but is important for its ability to fully respond to DNA damage. In this report, we determined that transient depletion of FANCJ adversely affects stability of FANCD2 and its co-regulator FANCI in multiple cell lines. Loss of FANCJ does not significantly alter cell cycle progression or FANCD2 transcription. However, in the absence of FANCJ, the majority of FANCD2 is degraded by both the proteasome and Caspase-3 dependent mechanism. FANCJ is capable of complexing with and stabilizing FANCD2 even in the absence of a functional helicase domain. Furthermore, our data demonstrate that FANCJ is important for FANCD2 stability and proper activation of DNA damage responses to replication blocks induced by hydroxyurea.


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