DDB1 is essential for genomic stability in developing epidermis

Cang, Yong; Zhang, Jianxuan; Nicholas, Sally A.; Kim, Arianna L.; Zhou, Pengbo; Goff, Stephen P.

doi:10.1073/pnas.0611311104

Cited by 59 publications

(64 citation statements)

References 38 publications

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“…We previously reported that DDB1 is essential for survival of proliferating cells in mouse brain and skin, but dispensable for nondividing cells such as neurons (21,22). Although highly differentiated, hepatocytes can reenter cell cycle and self-renew in response to loss of liver mass.…”

Section: Resultsmentioning

confidence: 99%

“…TUNEL-positive apoptotic cells were detected in regenerating livers but became more abundant in livers repopulated with DDB1-expressing hepatocytes (Fig. 2D), suggesting that DDB1-depleted hepatocytes, unlike DDB1-depleted neuronal and epidermal progenitor cells (21,22), do not undergo immediate apoptotic death but can survive for a very long time, presumably to maintain liver structural integrity and metabolic functions. No tissue necrosis (on histologic examination) or cell senescence (based on senescent β-galactosidase staining) were found during the regenerative process.…”

Section: Ddb1-expressing Hepatocytes Replace Ddb1-deficient Hepatocytesmentioning

confidence: 99%

“…In cultured cells (26) and developing embryos (22), loss of DDB1 causes genomic instability, which is associated with cancer disposition. Surprisingly, cancer cells in the liver tumors from DDB1 F/F ;Alb-Cre +/− mice apparently contained the parental floxed DDB1 allele rather than the deleted allele, judged from four experimental observations.…”

Section: Ddb1-expressing Hepatocytes Replace Ddb1-deficient Hepatocytesmentioning

confidence: 99%

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Hepatocyte-specific deletion of DDB1 induces liver regeneration and tumorigenesis

Yamaji

Zhang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Etiologic risk factors for hepatocellular carcinoma can be involved in the transformation process by directly targeting intracellular signaling pathways or by indirectly stimulating chronic cycles of hepatocyte destruction and regeneration. However, the contribution of these two routes to hepatocarcinogenesis has not been determined, partly because of the difficulty in distinguishing damaged and regenerated hepatocytes. Here we report that induced deletion of the damaged DNA binding protein 1 (DDB1) abrogates the self-renewing capacity of hepatocytes, resulting in compensatory proliferation of DDB1-expressing hepatocytes. Constitutive stimulation of this regeneration process leads to development of hepatocellular carcinoma, which surprisingly contains no disruption of the DDB1 gene, indicating a cell-nonautonomous role of DDB1 inactivation in tumor initiation. Our results suggest that viruses and hepatoxins may cause liver tumors by simply driving hepatocyte turnover without directly targeting cancer cells. of all primary liver cancers, is the fifth most common cancer and the third leading cause of cancer death worldwide (1). HCC development follows a multistep progression from hepatic dysplasia to neoplasia, with accumulation of somatic mutations and chromosomal alterations (2). Conventionally, these genetic alterations are identified in human liver tumor samples by gene expression profiling, genomic and proteomic analysis, and direct sequencing. Candidate genes are subsequently validated in cell cultures and animals. This methodology has led to the identification of oncogenes and tumor suppressor genes important for liver tumor development, such as those regulating Wnt/β-catenin, p53, EGFR receptor tyrosine kinases, and MET/HGF pathways (3).Alternatively, interactions between host factors and HCC-associated pathogens such as hepatitis B virus (HBV) and hepatitis C virus (HCV) can be investigated to understand early molecular and cellular alterations leading to HCC initiation. HBV encodes a nonstructural regulatory protein, HBx, that is required for HBV replication and implicated in HBV-associated HCC (4). How HBx contributes to hepatocarcinogenesis is unclear, but is believed to involve its myriad target host proteins, one of which is the damaged DNA binding protein 1 (DDB1) (5). DDB1 is the linker protein for the Cullin 4 (Cul4) E3 ubiquitin ligase (6), which regulates ubiquitination and proteasomal degradation of proteins essential for nucleotide excision repair [DDB2 (7) and CSB (8)], cell cycle progression [p21 (9, 10), p27 (11), and Myc (12)], DNA replication [Cdt1 (13) and POLH-1 (14)], and cell growth [c-Jun (15) and TSC2 (16)]. Other substrates of the E3 ligase, including XPC (7), histones H3 and H4 (17), and histone H2A (18), are modified without degradation to facilitate DNA damage repair. Several viral regulatory proteins such as the HIV Vpr protein (19) and the simian virus 5 V protein (20) can hijack the E3 ligase to target undesired host factors and benefit the respective viral life cycle.In this...

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Section: Resultsmentioning

confidence: 99%

Section: Ddb1-expressing Hepatocytes Replace Ddb1-deficient Hepatocytesmentioning

confidence: 99%

Section: Ddb1-expressing Hepatocytes Replace Ddb1-deficient Hepatocytesmentioning

confidence: 99%

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Hepatocyte-specific deletion of DDB1 induces liver regeneration and tumorigenesis

Yamaji

Zhang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…In fact, Cang et al recently showed that loss of DDB1 (which forms part of the Cul4A ubiquitin ligase core) from mouse brain, lens, or epidermis caused apoptosis in proliferating cells. 50,51 Similarities between these Cul4A-and DDB1-deficient phenotypes likely correspond with their encoded proteins being components of the same Cul4A ubiquitin ligases.…”

Section: Cul4a Is Essential and Deletion Causes Apoptosis 327mentioning

confidence: 99%

Cul4A is required for hematopoietic cell viability and its deficiency leads to apoptosis

Waning¹,

Li²,

Jia³

et al. 2008

Blood

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In vitro studies indicate that Cul4A ubiquitin ligases target for ubiquitin-mediated proteolysis regulators of cell-cycle progression, apoptosis, development, and DNA repair. In hematopoietic cell lines, studies by our group and others showed that Cul4A ligases regulate proliferation and differentiation in maturing myeloid and erythroid cells. In vivo, Cul4A-deficient embryos die in utero. Cul4A haploinsufficient mice are viable but have fewer erythroid and primitive myeloid progenitors. Yet, little more is known about Cul4A function in vivo. To examine Cul4A function in adults, we generated mice with interferon-inducible deletion of Cul4A. Cul4A deficiency resulted in DNA damage and apoptosis of rapidly dividing cells, and mutant mice died within 3 to 10 days after induction with dramatic atrophy of the intestinal villi, bone marrow, and spleen, and with hematopoietic failure. Cul4A deletion in vivo specifically increased cellular levels of the Cul4A ligase targets Cdt1 and p27Kip1 but not other known targets. Bone marrow transplantation studies with Cul4A deletion in engrafted cells specifically isolated analysis of Cul4A function to hematopoietic cells and resulted in hematopoietic failure. These recipients died within 9 to 11 days, demonstrating that in hematopoietic cells, Cul4A is essential for survival.

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“…The finding that CUL-4 orthologs in Drosophila and humans also negatively regulate the stability of CDK inhibitors of the CIP/KIP family provides the possibility that the latter pathway is also conserved. [49][50][51][52] What is the Role of CDKs in Regulating DNA Replication in Metazoa?…”

Section: Elegans Cul-4 Independently Regulates Both Cdc-6 and Cdt-mentioning

confidence: 99%

Control of the Cdc6 replication licensing factor in metazoa: The role of nuclear export and the CUL4 ubiquitin ligase

Kim¹,

Kipreos²

2008

Cell Cycle

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DDB1 is essential for genomic stability in developing epidermis

Cited by 59 publications

References 38 publications

Hepatocyte-specific deletion of DDB1 induces liver regeneration and tumorigenesis

Hepatocyte-specific deletion of DDB1 induces liver regeneration and tumorigenesis

Cul4A is required for hematopoietic cell viability and its deficiency leads to apoptosis

Control of the Cdc6 replication licensing factor in metazoa: The role of nuclear export and the CUL4 ubiquitin ligase

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