CRL Ubiquitin Ligases and DNA Damage Response

Abstract

Cullin/RING ubiquitin ligases (CRL) comprise the largest subfamily of ubiquitin ligases. CRLs are involved in cell cycle regulation, DNA replication, DNA damage response (DDR), development, immune response, transcriptional regulation, circadian rhythm, viral infection, and protein quality control. One of the main functions of CRLs is to regulate the DDR, a fundamental signaling cascade that maintains genome integrity. In this review, we will discuss the regulation of CRL ubiquitin ligases and their roles in control of the DDR.

Keywords: Cdc25A; Cdt1; DNA damage; claspin; cullin; cyclin D1; protein degradation; ubiquitin ligase.

Figure 1

Architecture of CRL1 (SCF) and CRL4 ubiquitin ligases. SCF ubiquitin ligases contain Cul1, Rbx1, Skp1, and F-box proteins which function as substrate receptors; whereas CRL4 has Cul4, Rbx1, DDB1, and DCAF proteins as substrate receptors. Both SCF and CRL4 can be activated by neddylation. F-box and DCAF proteins are substrate specificity factors.

Figure 2

Multiple kinases lead to the formation of phospho-degron of Cdc25A under DDR. Under DDR ATR activates Chk1 which then phosphorylates Cdc25A at S76 and turns on NEK11. Consequently, NEK11 phosphorylates Cdc25A at S82, whereas, CK1α phosphorylates both S79 and S82 of Cdc25A. In p53-deficient cells, p38MAPK and MK2 lead to the phosphorylation of S76 under UV damage. Upon the phospho-degron is created, Cdc25A is recognized and ubiquitinated by the SCF^βTRCP ubiquitin ligase.