Structural maintenance of chromosomes protein 1A (SMC1A) is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''SMC1A''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
SMC1A is a subunit of the
cohesin
Cohesin is a protein complex that mediates sister chromatid cohesion, homologous recombination, and DNA looping. Cohesin is formed of SMC3, SMC1, SCC1 and SCC3 ( SA1 or SA2 in humans). Cohesin holds sister chromatids together after DNA rep ...
complex which mediates
sister chromatid cohesion, homologous recombination and
DNA looping. In somatic cells, cohesin is formed of SMC1A,
SMC3
Structural maintenance of chromosomes protein 3 (SMC3) is a protein that in humans is encoded by the SMC3 gene. SMC3 is a subunit of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. Cohesin ...
,
RAD21 and either
SA1 or
SA2 whereas in meiosis, cohesin is formed of SMC3,
SMC1B
Structural maintenance of chromosomes protein 1B (SMC-1B) is a protein that in humans is encoded by the ''SMC1B'' gene. SMC-1B belongs to a family of proteins required for chromatid cohesion and DNA recombination during meiosis and mitosis.
SMC1ß ...
,
REC8
Meiotic recombination protein REC8 homolog is a protein that in humans is encoded by the ''REC8'' gene.
Rec8 is a meiosis-specific component of the cohesin complex that binds sister chromatids in preparation for the two divisions of meiosis. Rec8 ...
and
SA3.
SMC1A is a member of the
SMC protein family. Members of this family are key regulators of DNA repair, chromosome condensation and chromosome segregation from bacteria to humans.
Structure
![Structure of the interface between SMC1 (blue) and RAD21 (green) (PDB 1W1W) from budding yeast (Haering et al](https://upload.wikimedia.org/wikipedia/commons/3/36/Structure_of_the_interface_between_SMC1_%28blue%29_and_RAD21_%28green%29_%28PDB_1W1W%29_from_budding_yeast_%28Haering_et_al._2004%29.png)
The domain organisation of SMC proteins is highly conserved and is composed of an N-terminal
Walker A motif
The Walker A and Walker B motifs are protein sequence motifs, known to have highly conserved three-dimensional structures. These were first reported in ATP-binding proteins by Walker and co-workers in 1982.
Of the two motifs, the A motif is ...
, coiled-coil, "hinge", coiled-coil and a C-terminal
Walker B motif. The protein folds back on itself to form a rod-shaped molecule with a heterodimerisation "hinge" domain at one end and an
ABC-type ATPase "head" at the other. These globular domains are separated by a ~50 nm anti-parallel coiled-coil. SMC3 and SMC1 bind via their hinge domains creating V-shaped heterodimers. The N-terminal domain of RAD21 binds to the coiled coil of SMC3 just above the head domain while the C-terminal domain of RAD21 binds the head domain of SMC1. This end to end binding of the SMC3-SMC1-RAD21 trimer creates a closed ring within which DNA can be entrapped.
Function
In addition to entrapping DNA to ensure proper chromosome segregation during the cell cycle, SMC1A, as a component of cohesin, contributes to facilitating inter-chromatid contacts mediating distant-element interactions and to creating chromosome domains called topologically associating domains (TADs). It has been proposed that cohesin promotes the interaction between enhancers and promoters for regulating gene transcription regulation.
The removal of cohesin triggers abnormal TAD topology because loops spanning multiple compartment intervals lead to mixing among loci in different compartments
As a consequence, loop loss causes gene expression dysregulation.
SMC1A also plays a role in spindle pole formation. In fact, in association with SMC3, it is recruited to mitotic spindle poles through interaction with RAE1. The dysregulation of ''SMC1A'' (both down- and up-regulation) causes aberrant multi-polar spindles, suggesting that cohesin would function to hold microtubules at the spindle pole.
Proper cohesion of
sister chromatid
A sister chromatid refers to the identical copies (chromatids) formed by the DNA replication of a chromosome, with both copies joined together by a common centromere. In other words, a sister chromatid may also be said to be 'one-half' of the dup ...
s is a prerequisite for the correct segregation of
chromosome
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
s during cell division. The
cohesin
Cohesin is a protein complex that mediates sister chromatid cohesion, homologous recombination, and DNA looping. Cohesin is formed of SMC3, SMC1, SCC1 and SCC3 ( SA1 or SA2 in humans). Cohesin holds sister chromatids together after DNA rep ...
multiprotein complex is required for sister chromatid cohesion. This complex is composed partly of two structural maintenance of chromosomes (SMC) proteins, SMC3 and either
SMC1L2 or the protein encoded by this gene. Most of the cohesin complexes dissociate from the chromosomes before mitosis, although those complexes at the kinetochore remain. Therefore, the encoded protein is thought to be an important part of functional kinetochores. In addition, this protein interacts with
BRCA1
Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a h ...
and is
phosphorylated
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, whi ...
by
ATM, indicating a potential role for this protein in
DNA repair
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dam ...
. This gene, which belongs to the SMC gene family, is located in an area of the
X-chromosome
The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex- ...
that escapes
X inactivation
X-inactivation (also called Lyonization, after English geneticist Mary Lyon) is a process by which one of the copies of the X chromosome is inactivated in therian female mammals. The inactive X chromosome is silenced by being packaged into a ...
.
Clinical significance
Cornelia de Lange syndrome
Cornelia de Lange syndrome (CdLS) is a rare genetic disorder that presents with variable clinical abnormalities including
dysmorphic feature
A dysmorphic feature is an abnormal difference in body structure. It can be an isolated finding in an otherwise normal individual, or it can be related to a congenital disorder, Genetics, genetic syndrome or birth defect. Dysmorphology is the stud ...
s, severe growth retardation,
global developmental delay
Global developmental delay is an umbrella term used when children are significantly delayed in their cognitive development, cognitive and developmental biology, physical development. It can be diagnosed when a child is delayed in one or more milest ...
, and
intellectual disability
Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation,Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signifi ...
. The frequency varies from 1:10 000 to 1:30 000 live births without differences between ethnic groups.
SMC1A is one of five genes that have been implicated in CdLS. Pathogenic variants in ''SMC1A'', missense and small in frame deletions, are associated with CdLS. ''SMC1A'' variants, which maintain the frame of their encoded proteins, are associated with milder CdLS phenotypes with moderate neurocognitive disability and a paucity of major structural defects. The phenotype of ''SMC1A'' affected males is more severe than that of mutated females.
Since ''SMC1A'' escapes X inactivation, it has been hypothesized that the mechanism in affected females is the dominant-negative effect of the mutated protein.
Genome instability and cancer
''SMC1A'' also takes part in DNA repair. The down-regulation of ''SMC1A'' causes genome instability, and CdLS cells carrying ''SMC1A'' variants display high level of chromosome aberrations.
Furthermore, SMC1A is phosphorylated on Ser957 and Ser966 residues by ATM and ATR threonine/serine kinases following DNA damage induced by chemical treatment or ionizing radiation. It has been hypothesized that the Breast cancer type 1 susceptibility (BRCA1) gene collaborates in phosphorylating SMC1A, which is required for activation of the S-phase checkpoint allowing blocking of the cell cycle and the repair of DNA.
''SMC1A'' variants have been identified in blood, brain, bladder, and colon cancer.
''SMC1A'' plays a pivotal role in colorectal tumorigenesis. Indeed, colorectal tissue acquires extra-copies of ''SMC1A'' during cancer development and its expression is significantly stronger in carcinomas than in normal mucosa and early adenoma.
Finally, the up-regulation of ''SMC1A'' is thought to be a predictor of poor prognosis in colorectal cancer.
Notes
References
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