Alternative titles; symbols
HGNC Approved Gene Symbol: DYNLL1
Cytogenetic location: 12q24.31 Genomic coordinates (GRCh38): 12:120,469,842-120,498,493 (from NCBI)
DYNLL1 was originally identified as a light chain of the dynein motor complex with a role in dynein assembly. However, DYNLL1 has since been found to be a multifunctional regulator of protein dimerization that binds TQT motifs in proteins involved in various functions, including gene transcription, DNA damage response, apoptosis, synaptic transmission, cell migration, and nitric oxide signaling (summary by Jurado et al., 2012).
Dick et al. (1996) cloned dlc1, a Drosophila gene encoding a cytoplasmic dynein light chain. Sequence analysis revealed that dlc1 is very similar to the Chlamydomonas reinhardtii flagellar 8-kD dynein light chain, which is a component of the outer arm of the axonemal dynein. Partial loss-of-function dlc1 mutations caused pleiotropic morphogenetic defects in bristle and wing development and female sterility. The morphologic abnormalities found in the ovaries were associated with a loss of cellular shape and structure. Null mutations of dlc1 were lethal and caused embryonic degeneration and widespread apoptotic cell death. Dick et al. (1996) identified cDNAs encoding human and C. elegans homologs of dlc1. The predicted 89-amino acid human protein, DLC1, is 94% identical to dlc1. Using immunofluorescence, the authors demonstrated that epitope-tagged DLC1 is localized in the cytoplasm of mammalian cells. Northern blot analysis revealed that DLC1 is expressed as a major 0.7-kb and a minor 2.5-kb transcript in a variety of human tissues. Dick et al. (1996) stated that DLC1 has been shown to be a previously unsuspected component of highly purified bovine cytoplasmic dynein.
Nitric oxide (NO) is a major messenger molecule in the cardiovascular, immune, and nervous systems. In the brain, NO is responsible for the glutamate-linked enhancement of 3-prime, 5-prime cyclic guanosine monophosphate levels and may be involved in apoptosis, synaptogenesis, and neuronal development. Unlike other neurotransmitters NO cannot be stored in vesicles. Therefore, its release is regulated by the activity of the enzyme neuronal NO synthase (nNOS; 163731). By means of a yeast 2-hybrid screen, Jaffrey and Snyder (1996) found that the 10-kD human DLC1 protein physically interacts with and inhibits the activity of neuronal NOS. DLC1, designated by them PIN (for 'protein inhibitor of nNOS'), appeared to be one of the most conserved proteins in nature, showing 92% amino acid identity with the nematode and rat homologs. Binding of PIN destabilized the nNOS dimer, a conformation necessary for activity. These results suggested that PIN may regulate numerous biologic processes through its effects on nitric oxide synthase activity.
Using yeast 2-hybrid analysis with the postsynaptic scaffold protein gephyrin (GPH; 603930) as bait, Fuhrmann et al. (2002) identified rat dynein light chain-1 (Dlc1). Coimmunoprecipitation and GST pull-down assays confirmed that Dlc1 binds with Gph, and yeast 2-hybrid analysis showed that Dlc1 binds to residues 181-243 of Gph, in the central linker domain.
Using immunofluorescence, Fuhrmann et al. (2002) showed that both recombinant and endogenous Dlc1 colocalize with Gph in HEK293 cells. In primary hippocampal neurons, Dlc1 localized to the cytoplasm in a granular staining pattern and to the plasma membrane of dendrites and cell bodies in a punctate staining pattern. The pattern of Dlc1 membrane staining overlapped that of synaptophysin (313475) and partially overlapped that of Gph. Electron microscopy of spinal cord neurons showed that Dlc1 localizes to the edges of postsynaptic differentiations, along cytoskeletal structures, and at the edge of the Golgi apparatus. Wildtype Gph and Gph lacking the Dlc-binding domain expressed in hippocampal neurons showed similar staining patterns, suggesting that Dlc1 binding is not required for Gph localization.
Kaiser et al. (2003) found that 2 distinct regions of the nuclear transcription factor TRPS1 (604386) can physically interact with DNCL1. Region A covers 89 amino acids (635-723), spanning 3 potential C2H2 zinc finger structures, and region B covers the 100 most C-terminal amino acids (1182-1281) containing the IKAROS-like motif. DNCL1 colocalized with TRPS1 in dot-like structures in the cell nucleus. An electrophoretic mobility shift assay showed that the interaction of DNCL1 and TRPS1 lowered the binding of TRPS1 to the GATA consensus sequence. In addition, a GATA-regulated reporter gene assay indicated that DNCL1 could suppress the transcriptional repression activity of TRPS1.
ASCIZ (ATMIN; 614693) is a zinc finger protein with roles in the DNA damage response and embryonic development. Jurado et al. (2012) found that knockdown of ASCIZ resulted in significantly reduced expression of DYNLL1 in mouse, chicken, and human cells. Yeast 2-hybrid analysis revealed that DYNLL1 bound to both isoforms of ASCIZ. DYNLL1 bound to each of 10 single TQT motifs within the transactivation domain of ASCIZ, and DYNLL1 binding inhibited ASCIZ-dependent transactivation of a reporter gene. Chromatin immunoprecipitation analysis revealed that ASCIZ bound directly to the human DYNLL1 promoter and regulated its activity in a manner dependent on the ASCIZ zinc finger domain. However, high DYNLL1 levels inhibited the transcriptional activity of ASCIZ. DYNLL1 was also required for DNA damage-induced ASCIZ focus formation. Jurado et al. (2012) concluded that ASCIZ has the dual ability to activate DYNLL1 gene expression and to sense free DYNLL1 protein levels, resulting in simple feedback loop to adjust cellular content of DYNLL1.
He et al. (2018) identified DYNLL1 as an inhibitor of DNA end resection. The loss of DYNLL1 enables DNA end resection and restores homologous recombination in BRCA1 (113705)-mutant cells, thereby inducing resistance to platinum drugs and inhibitors of PARP (173870). Low BRCA1 expression correlated with increased chromosomal aberrations in primary ovarian carcinomas, and the junction sequences of somatic structural variants indicated diminished homologous recombination. Concurrent decreases in DYNLL1 expression in carcinomas with low BRCA1 expression reduced genomic alterations and increased homology at lesions. In cells, DYNLL1 limited nucleolytic degradation of DNA ends by associating with the DNA end-resection machinery (MRN complex, 617154; BLM helicase, 604610; and DNA2 endonuclease, 601810). In vitro, DYNLL1 bound directly to MRE11 (600814) to limit its end-resection activity. Therefore, He et al. (2018) inferred that DYNLL1 is an important antiresection factor that influences genomic stability and responses to DNA-damaging chemotherapy.
By fluorescence in situ hybridization, Dick et al. (1996) mapped the human DLC1 gene to 14q24. However, by genomic sequence analysis, Pazour et al. (2006) mapped the DLC1 gene to chromosome 12q24.23.
A report by Nunez et al. (2008) indicating that 3-dimensional motor-dependent interchromosomal interactions involving DLC1 are required to achieve enhanced transcription of specific estrogen-receptor target genes was retracted.
Dick, T., Ray, K., Salz, H. K., Chia, W. Cytoplasmic dynein (ddlc1) mutations cause morphogenetic defects and apoptotic cell death in Drosophila melanogaster. Molec. Cell. Biol. 16: 1966-1977, 1996. [PubMed: 8628263] [Full Text: https://doi.org/10.1128/MCB.16.5.1966]
Fuhrmann, J. C., Kins, S., Rostaing, P., El Far, O., Kirsch, J., Sheng, M., Triller, A., Betz, H., Kneussel, M. Gephyrin interacts with dynein light chains 1 and 2, components of motor protein complexes. J. Neurosci. 22: 5393-5402, 2002. [PubMed: 12097491] [Full Text: https://doi.org/10.1523/JNEUROSCI.22-13-05393.2002]
He, Y. J., Meghani, K., Caron, M.-C., Yang, C., Ronato, D. A., Bian, J., Sharma, A., Moore, J., Niraj, J., Detappe, A., Doench, J. G., Legube, G., Root, D. E., D'Andrea, A. D., Drane, P., De, S., Konstantinopoulos, P. A., Masson, J.-Y., Chowdhury, D. DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells. Nature 563: 522-526, 2018. [PubMed: 30464262] [Full Text: https://doi.org/10.1038/s41586-018-0670-5]
Jaffrey, S. R., Snyder, S. H. PIN: an associated protein inhibitor of neuronal nitric oxide synthase. Science 274: 774-777, 1996. [PubMed: 8864115] [Full Text: https://doi.org/10.1126/science.274.5288.774]
Jurado, S., Conlan, L. A., Baker, E. K., Ng, J.-L., Tenis, N., Hoch, N. C., Gleeson, K., Smeets, M., Izon, D., Heierhorst, J. ATM substrate Chk2-interacting Zn(2+) finger (ASCIZ) is a bi-functional transcriptional activator and feedback sensor in the regulation of dynein light chain (DYNLL1) expression. J. Biol. Chem. 287: 3156-3164, 2012. [PubMed: 22167198] [Full Text: https://doi.org/10.1074/jbc.M111.306019]
Kaiser, F. J., Tavassoli, K., Van den Bemd, G.-J., Chang, G. T. G., Horsthemke, B., Moroy, T., Ludecke, H.-J. Nuclear interaction of the dynein light chain LC8a with the TRPS1 transcription factor suppresses the transcriptional repression activity of TRPS1. Hum. Molec. Genet. 12: 1349-1358, 2003. [PubMed: 12761050] [Full Text: https://doi.org/10.1093/hmg/ddg145]
Nunez, E., Kwon, Y.-S., Hutt, K. R., Hu, Q., Cardamone, M. D., Ohgi, K. A., Garcia-Bassets, I., Rose, D. W., Glass, C. K., Rosenfeld, M. G., Fu, X.-D. Nuclear receptor-enhanced transcription requires motor- and LSD1-dependent gene networking in interchromatin granules. Cell 132: 996-1010, 2008. Note: Retraction: Cell 134: 189 only, 2008. [PubMed: 18358812] [Full Text: https://doi.org/10.1016/j.cell.2008.01.051]
Pazour, G. J., Agrin, N., Walker, B. L., Witman, G. B. Identification of predicted human outer dynein arm genes: candidates for primary ciliary dyskinesia genes. (Letter) J. Med. Genet. 43: 62-73, 2006. [PubMed: 15937072] [Full Text: https://doi.org/10.1136/jmg.2005.033001]