Functions and regulation of the multitasking FANCM family of DNA motor proteins

Abstract

Members of the conserved FANCM family of DNA motor proteins play key roles in genome maintenance processes. FANCM supports genome duplication and repair under different circumstances and also functions in the ATR-mediated DNA damage checkpoint. Some of these roles are shared among lower eukaryotic family members. Human FANCM has been linked to Fanconi anemia, a syndrome characterized by cancer predisposition, developmental disorder, and bone marrow failure. Recent studies on human FANCM and its orthologs from other organisms have provided insights into their biological functions, regulation, and collaboration with other genome maintenance factors. This review summarizes the progress made, with the goal of providing an integrated view of the functions and regulation of these enzymes in humans and model organisms and how they advance our understanding of genome maintenance processes.

Keywords: BLM; FANCM; Fml1; MHF; Mph1; crossover control; replication fork regression.

Figure 1.

The role of FANCM and partner proteins in coping with template lesions during DNA replication. MHF forms a complex with FANCM and FAAP24 and stabilizes FANCM. This complex localizes to ICL sites through its DNA-binding attribute. FANCM carries out several FA-independent functions at ICL sites and in other replication blockage situations. FANCM–MHF promote ICL traversal, allowing replication to proceed past the lesion without repair. FANCM also can catalyze replication fork regression under certain circumstances. In addition, FANCM and FAAP24 interact with the checkpoint protein HCLK2 to activate the ATR checkpoint signaling pathway (other means by which FANCM can promote checkpoint activation are not depicted here). In the FA pathway, FANCM–MHF–FAAP24 recruits the FA core complex to the ICL sites. The subsequent monoubiquitination of FANCI and FANCD2 leads to multiple repair steps, including ICL incision, DNA gap filling, and recombinational repair. The recruitment of the BLM–topoisomerase IIIα (Topo IIIα)–RMI (BTR) complex by FANCM enables double Holliday junction (dHJ) dissolution.

Figure 2.

The roles of FANCM family proteins in replication fork repair and crossover control. (A) Pathways that cope with replication blockage (denoted by the star), including error-prone translesion DNA synthesis and FANCM/Fml1/Mph1-mediated fork regression and subsequent recombination, are depicted. Note that Smc5/6 (structural maintenance of chromosomes 5/6) down-regulates Mph1's replication fork regression (or fork reversal) and DNA branch migration activities to prevent the generation of potentially harmful recombination intermediates, and Saccharomyces cerevisiae MHF (ScMHF) helps overcome this effect of Smc5/6. Two scenarios following fork reversal are shown. Following DNA synthesis, where one nascent strand uses the other to prime DNA synthesis, the fork can be reset, allowing replication resumption. Alternatively, the dsDNA ends can be resected to generate a substrate for invading the template strands that share sequence homology, generating a dHJ that requires resolution to allow replication resumption. Note that fork reversal can also lead to other outcomes that are not depicted here. (B) Model showing how FANCM family proteins promote DNA double-strand break repair via the synthesis-dependent strand annealing (SDSA) pathway that generates noncrossover products only. Repair via the double-strand break repair pathway (DSBR) leads to the formation of a dHJ intermediate that is resolved nucleolytically into crossover or noncrossover products. Alternatively, the dHJ can be dissolved by a helicase/topoisomerase complex composed of BTR or the yeast counterpart Sgs1/Top3/Rmi1 (STR), to yield noncrossover products. The dotted line denotes newly synthesized DNA.

Figure 3.

The FANCM family of DNA motor proteins. The domain structures of selected FANCM family proteins are indicated. These domains include the SF2 helicase domain (blue), MHF-binding region (yellow), RMI interaction region (pink), ERCC4 nuclease domain (gray; cross indicates the inactive nature of the domain), and HhH (a tandem helix–hairpin–helix; orange) domain. The MHF-binding domain on Mph1 (hatched) also interacts with Smc5/6. (Hs) Homo sapiens; (Mm) Mus musculus; (Dm) Drosophila melanogaster; (Sc) S. cerevisiae; (Sp) Schizosaccharomyces pombe; (Pfu) Pyrococcus furiosus.