Exploiting the Fanconi Anemia Pathway for Targeted Anti-Cancer Therapy

Abstract

Genome instability, primarily caused by faulty DNA repair mechanisms, drives tumorigenesis. Therapeutic interventions that exploit deregulated DNA repair in cancer have made considerable progress by targeting tumor-specific alterations of DNA repair factors, which either induces synthetic lethality or augments the efficacy of conventional chemotherapy and radiotherapy. The study of Fanconi anemia (FA), a rare inherited blood disorder and cancer predisposition syndrome, has been instrumental in understanding the extent to which DNA repair defects contribute to tumorigenesis. The FA pathway functions to resolve blocked replication forks in response to DNA interstrand cross-links (ICLs), and accumulating knowledge of its activation by the ubiquitin-mediated signaling pathway has provided promising therapeutic opportunities for cancer treatment. Here, we discuss recent advances in our understanding of FA pathway regulation and its potential application for designing tailored therapeutics that take advantage of deregulated DNA ICL repair in cancer.

Keywords: DNA interstrand cross-link; DNA repair; Fanconi anemia; cancer therapeutics; ubiquitin signaling.

Fig. 1.

Overview of the FA pathway. (A) A stalled replication fork at a DNA ICL activates the FA core complex to monoubiquitinate the FANCD2-FANCI heterodimer. (B) Ubiquitinated FANCD2 recruits a nuclease complex to initiate nucleolytic incisions flanking the ICL. (C) The unhooked lesion is processed and bypassed by TLS polymerases to restore a nascent leading strand. (D) Downstream FA proteins promote HR to repair double-stranded breaks, and the unhooked ICL is removed by NER. The USP1-UAF1 complex removes ubiquitin from FANCD2 to complete the repair.

Fig. 2.

Posttranslational modifications involved in the activation of FANCD2. (A) The FA core complex consists of three modules plus a lesion recognition unit, FANCM. Recognition of a DNA ICL by the FANCM-FAAP24-MHF complex activates ATR checkpoint signaling. (B) ATR and its effector CHK1 phosphorylate components of the FA core complex and the FANCD2-FANCI complex to control their activities. (C) The FANCB-FANCL-FAAP100 module constitutes a minimal catalytic core to monoubiquitinate FANCD2. FANCI phosphorylation potentiates FANCD2 activation. (D) ‘SUMO spray’ of FANC proteins may ensure balanced protein dosage required for the functional integrity of the FA pathway during DNA repair. For instance, FANCA and FANCD2 undergo controlled degradation by the integrated SUMO-ubiquitin signaling.

Fig. 3.

Strategies to exploit deregulated DNA repair for anticancer therapy. Deregulation of DNA repair leads to hyperdependency on a compensatory repair pathway or acquired platinum resistance due to an enhanced DNA repair capacity of cancer cells, which can be exploited by synthetic lethal interactions or resensitization to cross-linking agents.