Preventing Nonhomologous End Joining Suppresses DNA Repair Defects of Fanconi Anemia

Abstract

Fanconi anemia (FA) is a complex cancer susceptibility disorder associated with DNA repair defects and infertility, yet the precise function of the FA proteins in genome maintenance remains unclear. Here we report that C. elegans FANCD2 (fcd-2) is dispensable for normal meiotic recombination but is required in crossover defective mutants to prevent illegitimate repair of meiotic breaks by nonhomologous end joining (NHEJ). In mitotic cells, we show that DNA repair defects of C. elegans fcd-2 mutants and FA-deficient human cells are significantly suppressed by eliminating NHEJ. Moreover, NHEJ factors are inappropriately recruited to sites of replication stress in the absence of FANCD2. Our findings are consistent with the interpretation that FA results from the promiscuous action of NHEJ during DNA repair. We propose that a critical function of the FA pathway is to channel lesions into accurate, as opposed to error-prone, repair pathways.

Pro-crossover factors regulate damage-dependent apoptosis in the Caenorhabditis elegans germ line

“…As a consequence, mutants of either gene have a significant increase of germnuclei apoptosis that is cep-1 and spo-11 dependent. 27,28 We investigated whether apoptosis in these mutants also required MSH-4. Both brc-1;msh-4 and fcd-2;msh-4 double mutants display apoptotic levels lower than the brc-1 and fcd-2 single mutants (Figure 5a).…”

“…25,26 Mutants of DNA repair genes, such as rad-51, brc-1 (orthologue of human BRCA1), or fcd-2 (orthologue of human FANCD2), show elevated levels of apoptosis that are spo-11 and cep-1 dependent. 14,27,28 Similarly, mutants deficient in structural components of the SC, such as syp-2, 19 show an increase in germ-nuclei apoptosis that is in part dependent on the DNA damage checkpoint and in part on the synapsis checkpoint. 15 Worms carrying mutations in CO-promoting factors, such as him-14 (the C. elegans orthologue of Msh4; called msh-4 hereafter), msh-5, and zhp-3, show an abnormal accumulation of RAD-51 foci that are interpreted as unresolved recombination intermediates.…”

Regulation of Recombination and Genomic Maintenance

“…1), a particularly pernicious lesion, as repair by NHEJ or aEJ/ MMEJ will inevitably lead to genomic rearrangements. Interestingly, the Fanconi pathway (Kim and D'Andrea 2012) appears to be involved in inhibiting NHEJ in S phase (Adamo et al 2010;Pace et al 2010). This activity was unveiled by finding that Caenorhabditis elegans or human FANCD2-deficient cells are substantially suppressed for their interstrand cross-link sensitivity by eliminating NHEJ.…”

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

“…Other reports describing inhibitors of BER, HR and mismatch repair pathways offer further prospects for targeted cancer therapies (Bentle et al, 2006;Kelley and Fishel, 2008;Lieberman, 2008). Platinum compounds are the key drugs for the treatment of cancers defective in FA-BRCA pathway; however, recent reports describe that hypersensitivity of FA-deficient cells to crosslinking agents can be suppressed by the inhibition of NHEJ, possibly owing to reactivation of HR (Adamo et al, 2010;Pace et al, 2010). Whether this can occur in human cancer in clinical situation is an important issue, which needs to be investigated extensively.…”