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

被引：52

作者：

Shabbeer, S. ^{[1
,2
]}

Omer, D. ^{[3
]}

Berneman, D. ^{[3
]}

Weitzman, O. ^{[3
]}

Alpaugh, A. ^{[1
]}

Pietraszkiewicz, A. ^{[1
]}

Metsuyanim, S. ^{[3
]}

Shainskaya, A. ^{[4
]}

Papa, M. Z. ^{[3
]}

Yarden, R. I. ^{[1
,2
,3
]}

机构：

[1] Georgetown Univ, Med Ctr, Dept Human Sci, SNHS, Washington, DC 20057 USA

[2] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA

[3] Chaim Sheba Med Ctr, Dept Surg Oncol, Lab Genom Applicat, IL-52621 Tel Hashomer, Israel

[4] Weizmann Inst Sci, Laraine & Alan A Fischer Lab Biol Mass Spectromet, IL-76100 Rehovot, Israel

来源：

ONCOGENE | 2013年 / 32卷 / 42期

关键词：

BRCA1; cyclin B; Cdc25; ubiquitination; proteasome; G2/M cell cycle checkpoint; E3 LIGASE ACTIVITY; KEN-BOX; BINDING; PHOSPHORYLATION; CHECKPOINT; RING; COMPLEX; DOMAIN; CHK1; B1;

D O I：

10.1038/onc.2012.522

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：5005 / 5016

页数：12

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