The Multifunctions of WD40 Proteins in Genome Integrity and Cell Cycle Progression

Abstract

Eukaryotic genome encodes numerous WD40 repeat proteins, which generally function as platforms of protein-protein interactions and are involved in numerous biological process, such as signal transduction, gene transcriptional regulation, protein modifications, cytoskeleton assembly, vesicular trafficking, DNA damage and repair, cell death and cell cycle progression. Among these diverse functions, genome integrity maintenance and cell cycle progression are extremely important as deregulation of them is clinically linked to uncontrolled proliferative diseases such as cancer. Thus, we mainly summarize and discuss the recent understanding of WD40 proteins and their molecular mechanisms linked to genome stability and cell cycle progression in this review, thereby demonstrating their pervasiveness and importance in cellular networks.

Keywords: DNA damage; WD40 protein; cell cycle; cell death.

Figure 1

The involvement of WD40 proteins in genome stability and cell cycle progression. Multiple WD40 proteins interact with DDB1, Atg proteins, Cyclin proteins and other proteins through their WD40 repeats in response to DNA damage and repair, autophagy, cell cycle progression and/or apoptosis. CSA, Cockayne syndrome A; CSAat1A/B, CSA-like proteins in Arabidopsis 1A and 1B; DDB2, Damaged DNA binding protein 2; L2DTL, Drosophila lethal(2) denticleless protein; TLE1-3, Transducin-like enhancer of split 1 to 3; EED, Embryonic ectoderm development protein; WDR5, WD40 repeat-containing protein 5; Apaf-1, Activation of apoptotic protease activating factor 1; WDR35/92, WD40 repeat-containing protein 35/92; TRAF7, Tumor necrosis factor receptor-associated factor; LRRK2, Leucine-rich repeat kinase 2; Vps41, Vacuolar protein sorting 41; Atg18, Autophagy-related protein 18; EPG-6, Ectopic PGL granules 6; AMBRA1, autophagy/beclin-1 regulator 1; ALFY, autophagy‐linked FYVE protein; FBXW1/5/7/8, F-box/WD repeat-containing protein 1, 5, 7 and 8; CDC20,Cell division cycle protein 20.

Figure 2

A model for the assembly of the CUL4-DDB1-WD40 ubiquitin ligase complex. CUL4 serves as a rigid scaffold, and directly contacts with DDB1 with its N-terminal domain. CUL4 can also recruit Rbx1 and the E2 ubiquitin-conjugating enzyme via its C-terminal domain. The DDB1 further binds a variety of WD40 proteins to form E3 ligases, recognizing different substrates in response to different cellular processes . S, substrate. Ub, ubiquitination.

Figure 3

The tumor necrosis factor (TNF) induced apoptosis pathway and the Fas-Fas ligand-mediated apoptosis pathway. The Fas, tumor necrosis factor receptor type 1 and 2 (TNFR1 and TNFR2) localize in the cell membrane. Numerous adaptor proteins and signal transducing molecules are involved in signal transduction initiated by the binding of the Fas ligand (FasL) to Fas and TNF to TNFR1 and TNFR2, respectively , . cIAPs, cellular inhibitors of apoptosis; FADD, Fas-associated death domain protein; JNK, c-Jun N-terminal kinase; MEKK, Mitogen-activated protein kinase kinase kinase; TRADD, TNF receptor-associated death domain protein; TRAF2, TNF receptor-associated factor 2.

Figure 4

The process of autophagy. The process of macroautophagy consists of three main stages: initiation of the formation of the isolation membrane/phagophore; elongation and completion of the mature autophagosome; and fusion of the autophagosome with the lysosome to form an autolysosome . A variety of WD40 proteins have been identified to involve this process, such as Atg18, EPG-6, WIPI4, AMBRA1, Vps15, ALFY and LYST.