Abstract
Common fragile sites (CFSs) are genomic regions frequently involved in cancer-associated rearrangements. Most CFSs lie within large genes, and their instability involves transcription- and replication-dependent mechanisms. Here, we uncover a role for the mitochondrial stress response pathway in the regulation of CFS stability in human cells. We show that FANCD2, a master regulator of CFS stability, dampens the activation of the mitochondrial stress response and prevents mitochondrial dysfunction. Genetic or pharmacological activation of mitochondrial stress signaling induces CFS gene expression and concomitant relocalization to CFSs of FANCD2. FANCD2 attenuates CFS gene transcription and promotes CFS gene stability. Mechanistically, we demonstrate that the mitochondrial stress-dependent induction of CFS genes is mediated by ubiquitin-like protein 5 (UBL5), and that a UBL5-FANCD2 dependent axis regulates the mitochondrial UPR in human cells. We propose that FANCD2 coordinates nuclear and mitochondrial activities to prevent genome instability.
Highlights
Common fragile sites (CFSs) are genomic regions frequently involved in cancer-associated rearrangements
The increased CFS gene transcription in FANCD2depleted cells was associated with increased CFS instability, as measured by fluorescence in situ hybridization (FISH) using probes to detect breaks at the FHIT/FRA3B and PARK2/FRA6E loci (Fig. 1b, c)
We found that integrated stress response (ISR) inhibition by ISRIB modestly reduced the TG-incited or carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-incited expression of CFS genes but did not prevent their induction in FANCD2-deficient cells, further suggesting that the CFS genes can be induced by a separate pathway (Fig. 6c, d)
Summary
Common fragile sites (CFSs) are genomic regions frequently involved in cancer-associated rearrangements. Failure to prevent or resolve R-loops and transcription-associated replication stress and DNA damage may be the cause of the genomic instability that underlies the cancer predisposition of FA patients. In addition to their nuclear functions, FANC proteins have been shown to play non-canonical roles in the regulation of mitochondrial function and redox metabolism[30]. Mitochondrial dysfunction is an important effector of the FA cellular and clinical phenotype[36,37], as tumor incidence and the hematopoietic defects in Fanc-deficient mice can be improved by antioxidant treatments[38,39] Whether these two independent functions in mitochondrial homeostasis and genome stability are mechanistically linked is unclear. Maintenance of the protein-folding environment within each compartment is required for proper organelle function[40]
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