Editors' ChoiceFANCONI ANEMIA

Seek and destroy—and discover

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Science Translational Medicine  22 Apr 2015:
Vol. 7, Issue 284, pp. 284ec66
DOI: 10.1126/scitranslmed.aab3129

At least 17 genes—including the famous BRCA tumor-suppressor genes—play a role in Fanconi anemia (FA), an inherited syndrome of bone marrow failure, developmental abnormalities, and predisposition to cancer. As expected with such bewildering genetic complexity, not all FA patients are created equally. Most are diagnosed in childhood due to physical malformations or bone marrow failure. However, intrigued by the peculiar late presentation of a young-adult who was diagnosed with FA at age 33, Xie et al. zeroed in on a new pathway of possible clinical relevance.

The patient’s physicians correctly suspected underlying FA because of the patient’s short stature, bone marrow dysfunction, and early-onset breast cancer. Genomic sequencing revealed two mutations in the most common FA-associated gene, FA complementation group A (FANCA). The FANCA protein is part of a nuclear core complex essential for function of the FA-BRCA signaling network, which maintains genomic stability by orchestrating DNA-damage repair during interphase, resolving entangled replication forks, and governing mitosis. One of the patient’s mutations, FANCAI939S, affected the protein domain that interacts with FANCA-associated protein 20 (FAAP20), which delivers FANCA to sites of DNA damage. FANCAI939S was unable to recruit FAAP20 and its downstream target, the DNA repair protein REV1. Still, FANCAI939S was able to activate other essential branches of the FA network, including monoubiquitination of the FA group D2 protein (FANCD2), which is essential for the recruitment of a cascade of DNA repair protein. Thus, the FANCAI939S mutation only partially crippled the multifaceted genome protector, perhaps explaining why the patient was not diagnosed with FA until adulthood.

In transfection experiments, the mutated FANCAI939S protein was consistently expressed at lower levels relative to wild-type FANCA. Furthermore, loss of FAAP20 binding exposed FANCA to sumoylation on lysine 921, which triggers ring finger protein 4 (RNF4)–dependent polyubiquitination of FANCA—a modification that earmarks FANCA for proteasomal degradation. Thus, the I939S mutation rendered FANCA unstable, likely because FAAP20 binding did not protect FANCA from proteolysis-promoting posttranslational modifications and unrestrained destruction through the RNF4 pathway. Xie et al. propose that this signaling cascade silences the FA network under physiological conditions once DNA damage has been repaired.

This work reminds us that mechanistic dissection of patient-derived mutations can be translationally rewarding. Functional dissection of the new FANCAI939S “separation-of-function” mutant unveiled new FA regulatory pathways and provided a plausible explanation for the patient’s clinical course. Together, these advances suggest that the manipulation of proteasomal degradation might prove clinically useful for selected FA patients.

J. Xie et al., RNF4-mediated polyubiquitination regulates the Fanconi anemia/BRCA pathway. J. Clin. Invest. 125, 1523–1532 (2015). [Full Text]

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