FANCM connects the genome instability disorders Bloom's Syndrome and Fanconi Anemia.
Fanconi Anemia (FA) and Bloom's Syndrome (BS) are genetic disorders characterized by overlapping phenotypes, including aberrant DNA repair and cancer predisposition. Here, we show that the FANCM gene product, FANCM protein, links FA and BS by acting as a protein anchor and bridge that targets key components of the FA and BS pathways to stalled replication forks, thus linking multiple components that are necessary for efficient DNA repair. Two highly conserved protein:protein interaction motifs in FANCM, designated MM1 and MM2, were identified. MM1 interacts with the FA core complex by binding to FANCF, whereas MM2 interacts with RM1 and topoisomerase IIIalpha, components of the BS complex. The MM1 and MM2 motifs were independently required to activate the FA and BS pathways. Moreover, a common phenotype of BS and FA cells-an elevated frequency of sister chromatid exchanges-was due to a loss of interaction of the two complexes through FANCM.
Deans
Andrew J
AJ
London Research Institute, Cancer Research UK, South Mimms, UK.
West
Stephen C
SC
D000595:Amino Acid Sequence; D000818:Animals; D001816:Bloom Syndrome / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004249:DNA Damage; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D004261:DNA Replication / Q000502:physiology / Q000528:radiation effects; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism; D005199:Fanconi Anemia / Q000235:genetics / Q000378:metabolism; D042822:Genomic Instability; D006801:Humans; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism; D012854:Sister Chromatid Exchange
D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; C097151:Bloom syndrome protein; C518295:FANCM protein, human; D004265:DNA Helicases; D053484:RecQ Helicases; D004264:DNA Topoisomerases, Type I