The PTEN phosphatase functions cooperatively with the Fanconi anemia proteins in DNA crosslink repair.
Fanconi anemia (FA) is a genetic disease characterized by bone marrow failure and increased cancer risk. The FA proteins function primarily in DNA interstrand crosslink (ICL) repair. Here, we have examined the role of the PTEN phosphatase in this process. We have established that PTEN-deficient cells, like FA cells, exhibit increased cytotoxicity, chromosome structural aberrations, and error-prone mutagenic DNA repair following exposure to ICL-inducing agents. The increased ICL sensitivity of PTEN-deficient cells is caused, in part, by elevated PLK1 kinase-mediated phosphorylation of FANCM, constitutive FANCM polyubiquitination and degradation, and the consequent inefficient assembly of the FA core complex, FANCD2, and FANCI into DNA repair foci. We also establish that PTEN function in ICL repair is dependent on its protein phosphatase activity and ability to be SUMOylated, yet is independent of its lipid phosphatase activity. Finally, via epistasis analysis, we demonstrate that PTEN and FANCD2 function cooperatively in ICL repair.
Department of Cell and Molecular Biology, University of Rhode Island, Kingston, Rhode Island, USA.
Elizabeth A
EA
Vuono
Department of Obstetrics, Gynecology, and Reproductive Biology, Michigan State University, Grand Rapids, Michigan, USA.
Ananda
A
Mukherjee
Department of Cell and Molecular Biology, University of Rhode Island, Kingston, Rhode Island, USA.
David A
DA
Vierra
Department of Cell and Molecular Biology, University of Rhode Island, Kingston, Rhode Island, USA.
Morganne M
MM
Adroved
Genome Stability Unit, St. Vincent's Institute, Fitzroy, VIC 3065, Australia.
Charlotte
C
Hodson
Genome Stability Unit, St. Vincent's Institute, Fitzroy, VIC 3065, Australia.|Department of Medicine, The University of Melbourne, Parkville, VIC 3010, Australia.
Andrew J
AJ
Deans
Department of Cell and Molecular Biology, University of Rhode Island, Kingston, Rhode Island, USA.
Niall G
NG
Howlett
D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D043171:Chromosomal Instability / Q000187:drug effects; D004265:DNA Helicases / Q000378:metabolism; D004260:DNA Repair; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism*; D045325:HCT116 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D016685:Mitomycin / Q000633:toxicity; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D058207:Sumoylation; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000378:metabolism; D054875:Ubiquitination; D000097869:Polo-Like Kinase 1
D018797:Cell Cycle Proteins; D002843:Chromatin; D004265:DNA Helicases; D052236:Fanconi Anemia Complementation Group D2 Protein; D051856:Fanconi Anemia Complementation Group Proteins; D006657:Histones; D016685:Mitomycin; D051059:PTEN Phosphohydrolase; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D000071857:Tumor Suppressor p53-Binding Protein 1; D000097869:Polo-Like Kinase 1; C499905:FANCD2 protein, human; C519921:FANCI protein, human; C468783:H2AX protein, human; C518295:FANCM protein, human