Ddb1-flox Mouse

Ddb1, short for damage-specific DNA binding protein 1, is a crucial component of the Cullin-RING finger ligase family, specifically forming the CUL4-DDB1 ubiquitin ligase complex. This complex is involved in protein ubiquitination, a process that tags proteins for degradation or modulates their function, and is pivotal in regulating many cellular processes such as the cell cycle, DNA repair, and transcriptional regulation [5].

Adipose-or BAT-specific Ddb1 knockout mice exhibit severely whitened brown adipose tissue (BAT) and decreased expression of thermogenic genes. These mice develop hypothermia when acutely cold-exposed at 4 °C and partial lipodystrophy on a high-fat diet, indicating Ddb1's role in preparing brown adipocytes for cold-induced thermogenesis [4].

In the context of disease, Cul4A-DDB1-mediated monoubiquitination of phosphoglycerate dehydrogenase (PHGDH) promotes colorectal cancer metastasis. CUL4B-DDB1-COP1-mediated downregulation of UTX, a histone demethylase, advances colorectal cancer progression. Also, targeting CRL4 (CUL4A/DDB1) suppresses chemoresistant ovarian cancer growth by inducing mitophagy [1,2,3].

In summary, Ddb1 is essential for multiple cellular processes, with its function elucidated through gene knockout models. These models have revealed its significance in brown adipose tissue thermogenesis and its implications in cancer-related processes such as metastasis and chemoresistance, highlighting its potential as a therapeutic target in cancer and other related diseases.