title: BRCA1 targets G2/M cell cycle proteins for ubiquitination and proteasomal degradation.
abstract: The BRCA1 tumor suppressor protein heterodimerizes with its partner protein, BARD1, via the RING domain present in both proteins. The heterodimer contains an E3 ubiquitin ligase activity and participates in multiple cellular functions such as cell cycle control, DNA repair and regulation of gene transcription, collectively aimed at maintaining genomic stability and tumor suppression. Yet, the precise role of BRCA1 E3 ligase in these cellular functions is poorly understood. We present data showing that BRCA1 ubiquitinates G2/M cell cycle proteins, cyclin B and Cdc25C, leading to their accelerated degradation via a mechanism that is independent of APC/C. BRCA1-dependent degradation of cyclin B and Cdc25C is reversed by proteasome inhibitors and is enhanced following DNA damage, which may represent a possible mechanism to prevent cyclin B and Cdc25C accumulation, a requirement for mitotic entry. Our data provide mechanistic insight into how BRCA1 E3 ligase activity regulates the G2/M cell cycle checkpoint and, thus, contributes to maintenance of genomic stability.
authors.affiliation: 1] Department of Human Science, SNHS, Georgetown University Medical Center, Washington, DC, USA [2] Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: S
authors.initials: S
authors.lastname: Shabbeer
authors.forename: D
authors.initials: D
authors.lastname: Omer
authors.forename: D
authors.initials: D
authors.lastname: Berneman
authors.forename: O
authors.initials: O
authors.lastname: Weitzman
authors.forename: A
authors.initials: A
authors.lastname: Alpaugh
authors.forename: A
authors.initials: A
authors.lastname: Pietraszkiewicz
authors.forename: S
authors.initials: S
authors.lastname: Metsuyanim
authors.forename: A
authors.initials: A
authors.lastname: Shainskaya
authors.forename: M Z
authors.initials: MZ
authors.lastname: Papa
authors.forename: R I
authors.initials: RI
authors.lastname: Yarden
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism*; D016195:G2 Phase; D055785:Gene Knockdown Techniques; D042822:Genomic Instability; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D061986:MCF-7 Cells / Q000187:drug effects / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D054730:Protein Interaction Domains and Motifs; D054829:RING Finger Domains; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D054875:Ubiquitination; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D019926:Cyclin B; D007976:Leupeptins; D061988:Proteasome Inhibitors; C100879:UBE2K protein, human; D044763:Ubiquitin-Conjugating Enzymes; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde