Alternative titles; symbols
HGNC Approved Gene Symbol: CHD1L
Cytogenetic location: 1q21.1 Genomic coordinates (GRCh38): 1:147,172,747-147,295,762 (from NCBI)
In response to DNA strand breaks, chromatin adopts a relaxed structure due to the addition of poly(ADP-ribose) (PAR) to chromatin proteins by PARP enzymes (see PARP1; 173870), and this relaxation facilitates the repair of DNA damage. CHD1L interacts with PAR and has a role in chromatin relaxation following DNA damage (Ahel et al., 2009).
By searching for genes in a region of chromosome 1q amplified in hepatocellular carcinoma (HCC; 114550), Ma et al. (2008) cloned CHD1L, which they designated ALC1. The deduced 897-amino acid protein contains an SNF2 (see 300012)-like N-terminal helicase domain, followed by a helicase superfamily C-terminal domain and a putative PAR-binding macro domain. Fluorescence-tagged ALC1 localized to the nucleus in transfected cells. Western blot analysis detected ALC1 at an apparent molecular mass of 98 kD.
Using RT-PCR, Chen et al. (2009) found that mouse Chd1l was highly expressed in brain, heart, lung, kidney, and stomach, with lower expression in liver and spleen.
By FISH, Ma et al. (2008) mapped the CHD1L gene to a region of chromosome 1q21 amplified in HCCs and other solid tumors.
Using immunohistochemical analysis, Ma et al. (2008) found that ALC1 was overexpressed in more than 50% of informative HCC cases, primary HCCs, and HCC cell lines. Transfection of ALC1 in human liver and HCC cell lines increased colony formation in soft agar compared with vector controls and increased tumorigenicity of these cell lines in nude mice. Overexpression of ALC1 facilitated DNA synthesis and promoted G1/S phase transition. ALC1 downregulated expression of the cell growth inhibitors p53 (TP53; 191170) and p21(Waf1) (CDKN1A; 116899) and the proapoptotic proteins caspase-3 (600636) and BAX (600040) and upregulated the cell cycle regulators CDK2 (116953) and cyclin E (CCNE1; 123837). Knockdown of ALC1 by RNA interference reduced the percentage of cells in S phase, reduced colony formation in soft agar, and inhibited the cell cycle at the G1/S checkpoint. Ma et al. (2008) concluded that ALC1 is an oncogene that plays a role in HCC pathogenesis.
Using immunoprecipitation analysis, Ahel et al. (2009) showed that human ALC1 bound PAR in vitro, and the interaction required the macro domain of ALC1. Epitope-tagged ALC1 immunoprecipitated endogenous PAR from transfected 293 cells, along with PARP1 and core nucleosome components. Mass spectroscopy also revealed the presence of several DNA repair enzymes in the immunoprecipitate. ALC1 showed weak ATPase activity on its own that was attributed to its helicase domain, and this activity was stimulated by the addition of DNA and nucleosomes. PARP1 also stimulated the ATPase activity of ALC1 in an NAD(+)- and DNA-dependent manner. Wildtype ALC1, but not an ATPase-dead mutant, promoted nucleosome sliding in an ATP-dependent manner. Endogenous ALC1 rapidly but transiently localized to sites of DNA damage, and this localization required ALC1 ATPase activity and functional PARP1. Ahel et al. (2009) concluded that ALC1 is a nucleosome-repositioning enzyme that is targeted to sites of DNA damage through its interaction with PAR, and that ALC1 functions to regulate chromatin during DNA repair.
Independently, Gottschalk et al. (2009) found that ALC1 was a chromatin-remodeling enzyme that was recruited to nucleosomes and activated in a manner dependent on poly(ADP-ribosylation).
Chen et al. (2010) found that expression of the small GTPase ARHGEF9 (300429) correlated with CHD1L overexpression in human HCCs. In vitro and in vivo functional studies in mice showed that CHD1L contributed to tumor cell migration, invasion, and metastasis by increasing cell motility and inducing filopodia formation and epithelial-mesenchymal transition via ARHGEF9-mediated CDC42 (116952) activation. Silencing of Arhgef9 expression by RNA interference abolished the invasive and metastatic abilities of Chd1l in mice.
Chen et al. (2009) created a stable line of transgenic mice ubiquitously expressing and transmitting expression of human CHD1L. At older ages (over 20 months), CHD1L transgenic mice spontaneously developed a variety of tumors at a higher rate than wildtype. These tumors included hepatocellular carcinoma, salivary acidic cell adenocarcinoma, rhabdomyosarcoma, gallbladder adenocarcinoma, and colon adenocarcinoma. CHD1L transgenic mice were also more prone to alcohol intoxication-induced hepatocyte lesions and liver tumors.
Ahel, D., Horejsi, Z., Wiechens, N., Polo, S. E., Garcia-Wilson, E., Ahel, I., Flynn, H., Skehel, M., West, S. C., Jackson, S. P., Owen-Hughes, T., Boulton, S. J. Poly(ADP-ribose)-dependent regulation by DNA repair by the chromatin remodeling enzyme ALC1. Science 325: 1240-1243, 2009. [PubMed: 19661379] [Full Text: https://doi.org/10.1126/science.1177321]
Chen, L., Chan, T. H. M., Yuan, Y.-F., Hu, L., Huang, J., Ma, S., Wang, J., Dong, S.-S., Tang, K. H., Xie, D., Li, Y., Guan, X.-Y. CHD1L promotes hepatocellular carcinoma progression and metastasis in mice and is associated with these processes in human patients. J. Clin. Invest. 120: 1178-1191, 2010. [PubMed: 20335658] [Full Text: https://doi.org/10.1172/JCI40665]
Chen, M., Huang, J., Hu, L., Zheng, B., Chen, L., Tsang, S. L., Guan, X. Transgenic CHD1L expression in mouse induces spontaneous tumors. PLoS One 4: e6727, 2009. Note: Electronic Article. [PubMed: 19701453] [Full Text: https://doi.org/10.1371/journal.pone.0006727]
Gottschalk, A. J., Timinszky, G., Kong, S. E., Jin, J., Cai, Y., Swanson, S. K., Washburn, M. P., Florens, L., Ladurner, A. G., Conaway, J. W., Conaway, R. C. Poly(ADP-ribosyl)ation directs recruitment and activation of an ATP-dependent chromatin remodeler. Proc. Nat. Acad. Sci. 106: 13770-13774, 2009. [PubMed: 19666485] [Full Text: https://doi.org/10.1073/pnas.0906920106]
Ma, N.-F., Hu, L., Fung, J. M., Xie, D., Zheng, B.-J., Chen, L., Tang, D.-J., Fu, L., Wu, Z., Chen, M., Fang, Y., Guan, X.-Y. Isolation and characterization of a novel oncogene, amplified in liver cancer 1, within a commonly amplified region at 1q21 in hepatocellular carcinoma. Hepatology 47: 503-510, 2008. [PubMed: 18023026] [Full Text: https://doi.org/10.1002/hep.22072]