Alternative titles; symbols
HGNC Approved Gene Symbol: BRSK2
Cytogenetic location: 11p15.5 Genomic coordinates (GRCh38): 11:1,389,934-1,462,689 (from NCBI)
While screening a placenta genomic library for repeat sequences in the downstream region of the H19 gene (103280), Miura et al. (1999) identified the BRSK2 gene, which they designated PEN11B. By RT-PCR of fetal brain mRNA, followed by 3-prime and 5-prime RACE, they cloned BRSK2 cDNA. The deduced protein contains 149 amino acids. Northern blot analysis detected a major 3.8-kb transcript and a minor 4.2-kb transcript expressed mainly in brain and pancreas, with weaker expression in testis. Expression was not detected in other tissues examined. Miura et al. (1999) found that BRSK2 was preferentially expressed from the maternal allele in placenta, but no allelic preference was detected in brain, liver, and kidney. They concluded that BRSK2 is an atypical imprinted gene.
By searching an EST database for sequences similar to yeast Cdr2, followed by screening a testis cDNA library, Lu et al. (2004) cloned BRSK2, which they called SAD1. The deduced 778-amino acid protein has a calculated molecular mass of 87 kD. Phylogenetic analysis indicated that BRSK2 belongs to the MARK (see 606511) subfamily of kinases. Northern blot analysis detected ubiquitous expression of a 3.5-kb transcript, with highest levels in brain and testis.
By Northern blot analysis of synchronized glioblastoma cells, Lu et al. (2004) readily detected BRSK2 at the G1/S boundary, with slightly increased expression approaching M phase, and reduced expression during the next G1 phase. However, Western blot analysis found relatively constant protein levels during the cell cycle. BRSK2 expressed in insect cells specifically phosphorylated WEE1A (193525), CDC25C (157680), and CDC25B (116949) in an in vitro assay, but a kinase-dead mutant (lys59 to ala) did not. Overexpression of BRSK2 in HeLa cells resulted in increased phosphorylation of CDC25C. DNA damage induced by ultraviolet (UV) irradiation or methyl methane sulfonate, but not by ionizing radiation, enhanced endogenous BRSK2 kinase activity in a caffeine-sensitive manner and caused translocation of BRSK2 from the cytoplasm to the nucleus. Overexpression of BRSK2 induced G2/M arrest in HeLa cells. Small interfering RNA against BRSK2 partly abrogated UV-induced G2/M arrest. Lu et al. (2004) concluded that BRSK2 acts as a checkpoint kinase upon DNA damage induced by UV irradiation or methyl methane sulfonate.
Miura et al. (1999) determined that the BRSK2 gene contains 7 exons and spans 2.3 kb.
By FISH, Miura et al. (1998) mapped the BRSK2 gene to chromosome 11p15.5.
Kishi et al. (2005) showed that SAD-A (BRSK2) and SAD-B (BRSK1; 609235), mammalian orthologs of a kinase needed for presynaptic differentiation in Caenorhabditis elegans, are required for neuronal polarization. Kishi et al. (2005) generated mice null for both SAD-A and SAD-B. Mice homozygous for deletion of only 1 gene were healthy and fertile, but double-knockout pups showed little spontaneous movement, were only weakly responsive to tactile stimulation, and died within 2 hours of birth. At embryonic day 19, principal divisions of brain, spinal cord, and peripheral nervous system had formed, but the forebrain was noticeably smaller in double-mutant embryos than in littermate controls. Double-mutant neurons often had a starburst morphology or processes that ran diagonally or tangentially rather than radially, and axons were difficult to distinguish from dendrites.
Kishi, M., Pan, Y. A., Crump, J. G., Sanes, Y. R. Mammalian SAD kinases are required for neuronal polarization. Science 307: 929-932, 2005. [PubMed: 15705853] [Full Text: https://doi.org/10.1126/science.1107403]
Lu, R., Niida, H., Nakanishi, M. Human SAD1 kinase is involved in UV-induced DNA damage checkpoint function. J. Biol. Chem. 279: 31164-31170, 2004. [PubMed: 15150265] [Full Text: https://doi.org/10.1074/jbc.M404728200]
Miura, K., Masuzaki, H., Ishimaru, T., Niikawa, N., Jinno, Y. A HhaI/BstUI polymorphism in a novel gene at human chromosome 11p15.5. J. Hum. Genet. 43: 283-284, 1998. [PubMed: 9852686] [Full Text: https://doi.org/10.1007/s100380050092]
Miura, K., Miyoshi, O., Yun, K., Inazawa, J., Miyamoto, T., Hayashi, H., Masuzaki, H., Yoshimura, S., Niikawa, N., Jinno, Y., Ishimaru, T. Repeat-directed isolation of a novel gene preferentially expressed from the maternal allele in human placenta. J. Hum. Genet. 44: 1-9, 1999. [PubMed: 9929968] [Full Text: https://doi.org/10.1007/s100380050096]