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Review
. 2020 May 25;11(5):585.
doi: 10.3390/genes11050585.

The FANC/BRCA Pathway Releases Replication Blockades by Eliminating DNA Interstrand Cross-Links

Xavier Renaudin  1   2 , Filippo Rosselli  1   2
Affiliations
Review

The FANC/BRCA Pathway Releases Replication Blockades by Eliminating DNA Interstrand Cross-Links

Xavier Renaudin et al. Genes (Basel). .

Abstract

DNA interstrand cross-links (ICLs) represent a major barrier blocking DNA replication fork progression. ICL accumulation results in growth arrest and cell death-particularly in cell populations undergoing high replicative activity, such as cancer and leukemic cells. For this reason, agents able to induce DNA ICLs are widely used as chemotherapeutic drugs. However, ICLs are also generated in cells as byproducts of normal metabolic activities. Therefore, every cell must be capable of rescuing lCL-stalled replication forks while maintaining the genetic stability of the daughter cells in order to survive, replicate DNA and segregate chromosomes at mitosis. Inactivation of the Fanconi anemia/breast cancer-associated (FANC/BRCA) pathway by inherited mutations leads to Fanconi anemia (FA), a rare developmental, cancer-predisposing and chromosome-fragility syndrome. FANC/BRCA is the key hub for a complex and wide network of proteins that-upon rescuing ICL-stalled DNA replication forks-allows cell survival. Understanding how cells cope with ICLs is mandatory to ameliorate ICL-based anticancer therapies and provide the molecular basis to prevent or bypass cancer drug resistance. Here, we review our state-of-the-art understanding of the mechanisms involved in ICL resolution during DNA synthesis, with a major focus on how the FANC/BRCA pathway ensures DNA strand opening and prevents genomic instability.

Keywords: DNA repair; FANC/BRCA pathway; genomic instability; interstrand cross-link (ICL).

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Conflict of interest statement

The authors declare no conflicting financial interests.

Figures

Figure 1
Figure 1
Main DNA repair pathways. (A) base excision repair (BER), nucleotide excision repair (NER) and mismatch repair (MMR) repair damaged or mismatched bases. Lesions are recognized and excised, creating a relatively small gap (1–30 nt) that will be filled by a DNA polymerase; (B) nonhomologous end-joining (NHEJ, left) or homologous recombination repair (HRR, right) mediate double-strand break repair. NHEJ seals the breaks with compatible extremities. Incompatible extremities can lead to either a perfect repair or to mutations (base insertions or deletions). HRR starts with the resection of the extremities. Resected extremities are used for strand invasion, homology search and D-loop formation in the sister chromatid, allowing perfect repair of the double-strand break; (C) HRR safeguards replication. At a stalled replication fork, a single-strand break is generated to allow the subsequent resection and strand invasion in a process named break-induced replication (BIR).
Figure 2
Figure 2
Fanconi anemia/breast cancer-associated (FANC/BRCA) pathway in five modules. Module 1 is composed of the FANCM protein and its partners. FANCM acts as both a translocase and a cargo protein and binds DNA in close proximity to the lesion. Then, module 1 recruits module 2, which is composed of the FANC core complex proteins (names indicated in white) and the E2-ubiquitin ligase UBE2T. The FANC core complex is an E3-ubiquitin ligase, of which FANCL is the catalytic subunit. In response to an DNA interstrand cross-link (ICL), FANCL transfers a ubiquitin moiety from UBE2T onto module 3 proteins (FANCD2 and FANCI). In turn, monoubiquitinated FANCD2 and FANCI, among others, coordinate the recruitment of the proteins of Module 4 to perform ICL removal and restart replication. Once the repair is terminated, module 5 (USP1 and its partners) terminates the reaction by deubiquitinating FANCD2 and FANCI.
Figure 3
Figure 3
Models of interstrand cross-link (ICL) repair. (A) A moving replication fork meets an ICL and stalls. Therefore, by cutting the DNA on one strand, a one-ended double-strand break (DSB) is formed. The ICL is unhooked, forming an ssDNA patch with the ICL on the strand opposite to the DSB (A′). Replication restarts with a possible insertion of an incorrect base in front of the ICL (A′′. After DSB resection, replication resumes from the other sister chromatid using BIR and the repaired chromatid as a template leading, in the end, after the ICL is completely unhooked, to an eventual a mutation on both sister chromatids (A′′′); (B) A stalled fork is stabilized until the arrival, from the other side of the ICL, another, convergent fork. Subsequently, at both stalled forks, a one-ended DSB is created, similar to a canonical two-ended DSB, but separated by a 30–40 nucleotide gap that will be rescued by homologous recombination repair (HRR) after the reconstruction of the opposite strand; (C) When the replication fork encounters an ICL, the replisome can traverse the lesion without repairing it to continue DNA replication. Later, the ICL will be unhooked (C′), eventually creating, as described above, a one- or two-ended DSB that will be repaired by HRR; (D) Alternatively, FANCM can stabilize and reverse the fork(s), allowing time for ICL unhooking before reestablishment of the fork and the “traverse” of the lesion. As in A and B, the repair and replication rescue mediated by pathways C and D lead to the risk of generating and fixing mutations in the duplicated DNA. Red stars indicate the induction of possible mutations by translesional synthesis (TLS) polymerases.
Figure 4
Figure 4
DNA interstrand cross-link (ICL)-repair decision process. Schematic showing the various options offered to a cell when a replication fork faces an ICL. The schematic describes the choices to repair the ICL and the associated DSB until replication is able to resume. The colors illustrate the different paths available to a cell depending on the type of ICL repair.
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