Dna Damage RESPONSE Complexes to Sites of ICL Formation to Prevent Sister Chromatid Exchange

ReseaRch highlights

dNA dAmAGE RESPONSE complexes to sites of ICL formation to prevent sister chromatid exchange. This study reveals that FANCM Bridging genomic instability disorders bridges proteins of the Fanconi anaemia and Bloom’s syndrome pathways and A link between Fanconi anaemia can be caused by ICL encounter, but targets them to sites of DNA damage and Bloom’s syndrome, two genome not after ionizing radiation treatment. following replication fork collapse. instability disorders with similar To examine the effect of the interaction Further research into this area might phenotypes, has been identified. of FANCM with Fanconi anaemia core provide targets for the treatment of the The proteins encoded by the causal and Bloom’s syndrome proteins in the two genetic disorders. genes of both syndromes interact DNA damage response, FANCM lacking Rachel David following interstrand cross link (ICL) MM1 and/or MM2 was ectopically formation, and this is mediated by expressed in FANCM-deficient cells. ORIGINAL RESEARCH PAPER Dean, A. J. & FANCM, the only Fanconi anaemia Loss of MM1 and/or MM2 increased West, S. C. FANCM connects the genome instability disorders Bloom’s syndrome and core protein known to have intrinsic cell sensitivity to mitomycin C, an Fanconi anemia. Mol. Cell 36, 943–953 (2009) DNA-binding activity. ICL-inducing agent, indicating a FuRtHER REAdING Huen, M. S. Y., Sy, S. M. H. & Two evolutionarily conserved motifs requirement for both protein complexes Chen, J. BRCA1 and its toolbox for the in FANCM, MM1 and MM2, were in ICL repair. However, ubiquitylation of maintenance of genome integrity. Nature Rev. Mol. Cell Biol. 11, 138–148 (2010) identified that interact with the Fanconi the Fanconi anaemia protein FANCD2 anaemia core protein FANCF and the (mediated by the Fanconi anaemia core) Bloom’s syndrome proteins RM11 and the formation of FANCD2 foci, and topoisomerase IIIα, respectively. which promote ICL repair, occurred Loss of FANCM by small interfering independently of the presence of Bloom’s RNA prevented the association of syndrome proteins, as only loss of MM1 FANCF (and other Fanconi anaemia had an effect. Finally, both MM1 and core proteins) with Bloom’s syndrome MM2 were needed for the repair of sister proteins, confirming that FANCM chromatid exchanges (a phenotype of links the two protein complexes. patients with Bloom’s syndrome and Moreover, FANCM was required for a potential consequence of ICL). This the recruitment of Bloom’s syndrome suggests that the activation of this DNA proteins to DNA damage foci following damage response pathway requires the collapse of the replication fork, which coordinated recruitment of both protein