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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.

SUBMITTER: Shabbeer S

PROVIDER: S-EPMC3796024 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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BRCA1 targets G2/M cell cycle proteins for ubiquitination and proteasomal degradation.

Shabbeer S S Omer D D Berneman D D Weitzman O O Alpaugh A A Pietraszkiewicz A A Metsuyanim S S Shainskaya A A Papa M Z MZ Yarden R I RI

Oncogene 20121217 42

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 showin ...[more]

PMID: 23246971

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Project description:Aims: Colorectal cancer (CRC) has high mortality and morbidity rates; however, the mechanism of CRC cells uncontrolled proliferation is unclarified, E3 ligases are widely reported to have crucial functions in cancers. HERC3 was once recognized as an important role in CRC, however its effects on CRC cell proliferation and cell cycle are blank. Methods: Correlation between HERC3 and clinical characteristics was analyzed. Coimmunoprecipitation, mass spectrometry analysis and GST-pull down were performed to identify interacting-proteins of HERC3. Expression pattern of RPL23A and its correlation between HERC3 was researched via qRT-PCR, western blot and immunohistochemistry. In vivo and vitro gain-and loss-of-function assays and rescue experiments concentrating HERC3-RPL23A axis in terms of cell proliferation and cell cycle were conducted. The ubiquitination regulatory mechanism between HERC3 and RPL23A were identified via vivo ubiquitylation assays, cycloheximide analysis and mass spectrometry analysis. GSEA aided to research the potential functional mechanism of RPL23A and validated by western blot and in vivo ubiquitylation assays. Results: HERC3 expression decreased gradually from colorectal tissues in healthy individuals to adjacent-tumors normal tissue in CRC patients, and to tumor tissues and HERC3 could inhibit CRC cell proliferation and arrest cells in the G0-G1 phase. RPL23A which was recognized as one potential target of HERC3 was identified to be overexpressed in CRC and could serve as a prognostic biomarker in CRC. RPL23A could also independently regulate the cell cycle and cell proliferation and attenuate the influence of HERC3 on CRC. In addition, HERC3 directly interacted with RPL23A and served as an E3 ligase to ubiquitination degrade RPL23A via K48-dependant manner through the HECT domain. Furthermore, HERC3 could regulate the ubiquitination of p21 and further modulate protein expression of c-Myc and p21 via regulating RPL23A. Conclusion: HERC3 controlled CRC proliferation, the cell cycle and regulated the c-Myc/p21 axis via directly targeting RPL23A for ubiquitination degradation.

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BRCA1 targets G2/M cell cycle proteins for ubiquitination and proteasomal degradation.

Publications

BRCA1 targets G2/M cell cycle proteins for ubiquitination and proteasomal degradation.

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