Regulated degradation of FANCM in the Fanconi anemia pathway during mitosis.
The 13 Fanconi anemia (FA) proteins cooperate in a common DNA repair pathway. Eight of these proteins are assembled into a multisubunit E3 ligase called the FA core complex. During S phase, the FA core complex is loaded by the FANCM protein into chromatin where it monoubiquitinates its substrates. In mitosis, the FA core complex is released from FANCM by an unknown mechanism. Here we show that FANCM is hyperphosphorylated and degraded during mitosis. beta-TRCP and Plk1 are the key regulators of FANCM degradation. Nondegradable mutant forms of FANCM retain the FA core complex in the chromatin and disrupt the FA pathway. Our data provide a novel mechanism for the cell cycle-dependent regulation of the FA pathway.
Kee
Younghoon
Y
Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Kim
Jung Min
JM
D'Andrea
Alan D
AD
D'Andrea
Alan
A
D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D004265:DNA Helicases / Q000378:metabolism*; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism*; D042822:Genomic Instability; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008938:Mitosis / Q000502:physiology*; D046912:Multiprotein Complexes / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016415:Sequence Alignment; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism; D000097869:Polo-Like Kinase 1
D018797:Cell Cycle Proteins; D004265:DNA Helicases; D051856:Fanconi Anemia Complementation Group Proteins; D046912:Multiprotein Complexes; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D044767:Ubiquitin-Protein Ligases; D044844:beta-Transducin Repeat-Containing Proteins; D000097869:Polo-Like Kinase 1; C471644:BTRC protein, human; C518295:FANCM protein, human