The Fanconi Anemia Pathway Maintains Genome Stability by Coordinating Replication and Transcription

Abstract

SummaryDNA replication stress can cause chromosomal instability and tumor progression. One key pathway that counteracts replication stress and promotes faithful DNA replication consists of the Fanconi anemia (FA) proteins. However, how these proteins limit replication stress remains largely elusive. Here we show that conflicts between replication and transcription activate the FA pathway. Inhibition of transcription or enzymatic degradation of transcription-associated R-loops (DNA:RNA hybrids) suppresses replication fork arrest and DNA damage occurring in the absence of a functional FA pathway. Furthermore, we show that simple aldehydes, known to cause leukemia in FA-deficient mice, induce DNA:RNA hybrids in FA-depleted cells. Finally, we demonstrate that the molecular mechanism by which the FA pathway limits R-loop accumulation requires FANCM translocase activity. Failure to activate a response to physiologically occurring DNA:RNA hybrids may critically contribute to the heightened cancer predisposition and bone marrow failure of individuals with mutated FA proteins.

Detectable clonal mosaicism in blood as a biomarker of cancer risk in Fanconi anemia

“…[29][30][31] Elucidating the genomic features of breakpoint intervals of CMEs can provide information about the mechanisms underlying these rearrangements as well as the phenotypic consequences for the patient. The enrichment of coding genes in FA breakpoint intervals reinforces the growing evidence coupling transcriptional activity with DNA repair, 32,33 which is perturbed in FA patients. Importantly, we detected 2 CMEs in both blood and tumor (anal SCC) samples in 1 FA patient.…”

PARP-1 Expression Quantified by [18F]FluorThanatrace: A Biomarker of Response to PARP Inhibition Adjuvant to Radiation Therapy

“…10 Recently, the BRCA1/2 genes have been found to be identical to genes previously discovered within the Fanconi's anemia pathway, and they give rise to 18 additional genes that can lead to HR deficiency. 11 HR is one of the primary mechanisms for repairing DNA double-stranded breaks, and it utilizes complementary single-stranded DNA as a template for repair. Through HR, the genomic information is conserved, preventing DNA repair-associated mutagenesis.…”

BRCA2 functions: from DNA repair to replication fork stabilization

“…R-loop-linked genomic instability is particularly exacerbated in BRCA1/2 tumors cells as well as in cells isolated from FA patients (Kee & D'Andrea 2012, Hatchi et al 2015. Consistent with this observation, depletion of BRCA2, BRCA1 or the FAgenes (FANCD2, FANCA, FANCM, FANCL) lead to the accumulation of R-loop and to a concomitant increase in the number of chromosomal aberrations in these cells (Bhatia et al 2014, Garcia-Rubio et al 2015, Hatchi et al 2015, Schwab et al 2015. Nevertheless, it remains largely unclear how R-loops promote genomic instability in this context.…”

“…Thus, it is possible that BRCA2 collaborates with FA genes to limit the appearance of the RNA:DNA hybrids and its associated genomic instability. In these conditions, resolution of R-loops is dependent on the translocase activity of FANCM (Schwab et al 2015).…”