CUL4A Abrogation Augments DNA Damage Response and Protection against Skin Carcinogenesis

Abstract

SUMMARY It is intuitively obvious that the ability of a cell to repair DNA damage is saturable, either by limitation of enzymatic activities, the time allotted to achieve their function, or both. However, very little is known regarding the mechanisms that establish such a threshold. Here we demonstrated that the CUL4A ubiquitin ligase restricts the cellular repair capacity by orchestrating the concerted actions of nucleotide excision repair (NER) and the DNA damage-responsive G1/S checkpoint through selective degradation of the DDB2 and XPC DNA damage sensors and the p21/CIP1/WAF1 checkpoint effector. We generated Cul4a conditional knockout mice and observed that skin-specific Cul4a ablation dramatically increased resistance to UV-induced skin carcinogenesis. Our findings reveal that wild-type cells do not operate at their full DNA repair potential, underscore the critical role of CUL4A in establishing the cellular DNA repair threshold, and highlight the potential augmentation of cellular repair proficiency by pharmacological CUL4A inhibition.

Essential role of the CUL4B ubiquitin ligase in extra-embryonic tissue development during mouse embryogenesis

“…Among the CUL4 substrates that control cell cycle progression, the cyclin-dependent kinase inhibitor p21 was recently shown to be targeted for ubiquitination and degradation by both CUL4A and CUL4B under normal conditions as well as post-UV irradiation in cell lines [10,11]. However, primary mouse embryonic fibroblasts preferentially utilize CUL4A to restrict p21 levels [12], suggesting context-dependent degradation of p21 by the two CUL4 ubiquitin ligases. Cul4a null mice are viable and display no gross phenotypic abnormalities throughout their lifespan except for meiotic defects in male mice [12][13][14].…”

“…However, primary mouse embryonic fibroblasts preferentially utilize CUL4A to restrict p21 levels [12], suggesting context-dependent degradation of p21 by the two CUL4 ubiquitin ligases. Cul4a null mice are viable and display no gross phenotypic abnormalities throughout their lifespan except for meiotic defects in male mice [12][13][14]. Despite the largely overlapping functions of CUL4A and CUL4B, recent studies also revealed distinct roles for the two CUL4 family members in DNA-damage response, male meiosis, and response to environmental toxins [12][13][14][15].…”

“…Cul4a null mice are viable and display no gross phenotypic abnormalities throughout their lifespan except for meiotic defects in male mice [12][13][14]. Despite the largely overlapping functions of CUL4A and CUL4B, recent studies also revealed distinct roles for the two CUL4 family members in DNA-damage response, male meiosis, and response to environmental toxins [12][13][14][15]. While CUL4B compensates for the loss of CUL4A [12], CUL4A expression, which is unaffected by CUL4B mutations [16], is apparently unable to rescue the neuronal and developmental deficiencies found in CUL4B patients with XLMR.…”

Temporal regulation of autophagy response by the CULLIN 4-AMBRA1-CULLIN 5 axis

“…CULLIN 4 is known to play an important role in the response to DNA damage. 10 Interestingly, Cullin 4A mutant cells show an increased resistance to UVmediated DNA damage associated with a prolonged DNA repair response as a result of reduced degradation of DNA damage sensors, such as DDB2 and DNA repair protein complementing XP-C (XPC). 10 In light of our results, it is tempting to speculate that CULLIN 4 function may have evolved to temporally limit the induction of different stress pathways.…”

CUL4B ubiquitin ligase in mouse development: A model for human X-linked mental retardation syndrome?

“…CUL4A and CUL4B assemble structurally similar E3 complexes through binding to an adaptor protein (DDB1) and a substrate receptor protein (DCAF) at the N-terminus, and a RING protein RBX1 at the C-terminus (Figure 1), and share functional redundancy in targeting substrates such as p21 and Cdt1 for ubiquitination and degradation [1,2]. The Cul4a-null mice are viable and display no abnormal development and growth phenotypes, likely due to functional compensation from Cul4b [4,5]. The only phenotype associated with Cul4a abrogation is the reproductive defects seen with male but not female mice, resulting from differential non-overlapping expression patterns of the two Cul4 genes during male meiosis [6].…”