Disease relevance of SMC1A

• X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations [1].
• SB1.8 also exhibits regions of homology and overall structural similarity to the prokaryote (Mycoplasma hyorhinis) protein 115p [2].
• We have uncovered novel phenotypes caused by MRN deficiency that support a functional link between this complex, ATR and Smc1, including hypersensitivity to UV exposure, a defective UV responsive intra-S phase checkpoint and a specific pattern of genomic instability [3].
• Generation of mice and cells that are unable to phosphorylate SMC1 demonstrated the importance of SMC1 phosphorylation in the DNA-damage-induced S-phase checkpoint, in determining rates of repair of chromosomal breaks, and in determining cell survival after DNA damage [4].
• The antigrowth effect of the three alpha1-adrenoceptor antagonists was examined in two human prostate cancer cell lines, PC-3 and DU-145, and a prostate smooth muscle cell primary culture, SMC-1, on the basis of: (a) cell viability assay; (b) rate of DNA synthesis; and (c) induction of apoptosis [5].

High impact information on SMC1A

• To explore the functional importance of SMC1 phosphorylation, murine cells were generated, in which the two damage-induced phosphorylation sites in SMC1 are mutated [6].
• Using mass spectrometry, we established that ATM phosphorylates S957 and S966 of SMC1 in vivo [7].
• Structural maintenance of chromosomes (SMC) proteins (SMC1, SMC3) are evolutionarily conserved chromosomal proteins that are components of the cohesin complex, necessary for sister chromatid cohesion [7].
• Phosphorylation of S957 and/or S966 of SMC1 is required for activation of the S-phase checkpoint in response to IR [7].
• Human SMC5/6 complex promotes sister chromatid homologous recombination by recruiting the SMC1/3 cohesin complex to double-strand breaks [8].

Biological context of SMC1A

• Importantly, hSMC1 is targeted only to the active centromere on dicentric chromosomes [9].
• Localization of human SMC1 protein at kinetochores [9].
• These results suggest that hSMC1 is an integral component of the functional kinetochore structure during mitosis [9].
• The SMC1/3 cohesin complex is thought to promote HR by maintaining the close proximity of sister chromatids at DSBs [8].
• We found that a second complex, hSMC1/hSMC3, is required for metaphase progression in mitotic cells [10].

Anatomical context of SMC1A

• Both SMC1 and SMC3 localized to the cilia of retinal photoreceptors and Madin-Darby canine kidney cells, suggesting a broader physiological relevance of this interaction [11].
• RPGR-ORF15, which is mutated in retinitis pigmentosa, associates with SMC1, SMC3, and microtubule transport proteins [11].
• By investigating normal, ATM- and ATR-deficient cell lines, we provide evidence that the contribution of SMC1 in preventing the collapse of stalled replication fork is an Atr-dependent pathway [12].
• The DXS423E gene has been localized to Xp11.21 and is expressed in somatic cell hybrids retaining either the human active or inactive X chromosome, demonstrating that DXS423E escapes X chromosome inactivation [13].
• Transplantation of micromeres to animal cells resulted in the induction of SMC1-positive cells, pigment cells, blastocoelar cells and muscle cells [14].

Other interactions of SMC1A

• We show for the first time that MRN is required for ATR-dependent phosphorylation of structural maintenance of chromosomes 1 (Smc1), which acts within chromatin to ensure sister chromatid cohesion and to effect several DNA damage responses [3].
• The SMC1 protein appears to be a particularly important target of the ATM kinase, playing critical roles in controlling DNA replication forks and DNA repair after the damage [4].
• Cohesin, the Smc1/3 complex, mediates sister chromatid cohesion while two condensin complexes containing Smc2/4 facilitate chromosome condensation [15].
• So far, two genes (NIPBL and SMC1L1) have been identified causing CdLS or CdLS-like phenotypes [16].
• Thus the DXS423E and XE169 genes define a new region in the proximal short arm of the X chromosome that is not subject to X chromosome inactivation, supporting a regional basis for escape from inactivation [13].

Analytical, diagnostic and therapeutic context of SMC1A

• Despite its dissociation from chromosomes, however, microinjection of an antibody against human SMC1 led to disorganization of the metaphase plate and cell cycle arrest, indicating that human cohesin still plays an important role in metaphase [17].
• Co-immunoprecipitation revealed an interaction occurring between Smc1 and Mcm7, both in vitro and in vivo [18].
• Both DNA affinity and chromatin immunoprecipitation assays showed that OA treatment dissociates SMC1 from the CYP2B6 promoter, reciprocating the indirect binding of CAR to OARE [19].

References