CUL4A

CUL4A Full Name

cullin 4A

CUL4A Introduction

CUL4A (Cullin 4A) is a critical scaffolding protein that forms the core of the CRL4 (Cullin-RING Ligase 4) E3 ubiquitin ligase complex, which includes DDB1 as an adaptor, Rbx1 as the catalytic subunit, and various substrate receptors such as Cdt2. This complex plays a central role in maintaining genomic integrity by targeting key regulators of DNA replication and cell cycle progression for ubiquitin-mediated degradation, including Cdt1, p21, and Set8. The specificity of CRL4A-mediated ubiquitination is often guided by interactions with proliferating cell nuclear antigen (PCNA) and substrate degron motifs, ensuring that replication licensing and DNA damage responses are tightly coordinated, which is essential for preventing DNA re-replication and maintaining cellular homeostasis.

Functionally, CUL4A has emerged as a critical modulator of protein turnover in multiple cellular contexts, extending beyond DNA replication control. For example, in cancer cells, CUL4A directly mediates the ubiquitination and proteasomal degradation of tumor suppressor proteins such as ANXA10 in non-small cell lung cancer (NSCLC) and ST7 in colorectal cancer. These actions promote tumor cell proliferation, migration, and invasion, highlighting the oncogenic potential of CUL4A when overexpressed. Small molecules like NSC1892 that disrupt the interaction between CUL4A and DDB1 have been shown to stabilize tumor suppressor proteins, inhibit cancer cell growth, and demonstrate significant antitumor effects in vivo, emphasizing the therapeutic relevance of targeting this E3 ligase.

Clinically, aberrant expression or dysregulation of CUL4A is associated with poor prognosis and therapy resistance in multiple cancers. In platinum-resistant ovarian cancer, elevated CRL4A activity contributes to chemoresistance by impairing mitochondrial dynamics and function, whereas CRL4A depletion triggers mitophagy via the Parkin-PINK1 pathway, reducing ATP production and oxidative respiration. These findings suggest that targeting CUL4A—either directly or through its regulatory pathways—represents a promising strategy to enhance cancer treatment efficacy, overcome drug resistance, and restore normal cellular control over protein degradation and genomic stability.

Alternate Names for CUL4A

CUL4A; cullin 4A; cullin-4A; CUL-4A;

• 1.Mazian MA, et al.; CRL4Cdt2 Ubiquitin Ligase, A Genome Caretaker Controlled by Cdt2 Binding to PCNA and DNA. Genes (Basel). 2022, 13(2):266.
  2.Meng Y, et al.; Targeting CRL4 suppresses chemoresistant ovarian cancer growth by inducing mitophagy. Signal Transduct Target Ther. 2022, 7(1):388.