SMC complexes represent a large family of ATPases that participate in many aspects of higher-order chromosome organization and dynamics. [1] [2] [3] SMC stands for Structural Maintenance of Chromosomes.
SMC complexes represent a large family of ATPases that participate in many aspects of higher-order chromosome organization and dynamics. [1] [2] [3] SMC stands for Structural Maintenance of Chromosomes.
Eukaryotes have at least six SMC proteins in individual organisms, and they form three distinct heterodimers with specialized functions:
Each complex contains a distinct set of non-SMC regulatory subunits. Some organisms have variants of SMC proteins. For instance, mammals have a meiosis-specific variant of SMC1, known as SMC1β. [11] The nematode Caenorhabditis elegans has an SMC4-variant that has a specialized role in dosage compensation. [12]
The following table shows the SMC proteins names for several model organisms and vertebrates: [13]
| Subfamily | Complex | S. cerevisiae | S. pombe | C. elegans | D. melanogaster | Vertebrates |
|---|---|---|---|---|---|---|
| SMC1α | Cohesin | Smc1 | Psm1 | SMC-1 | DmSmc1 | SMC1α |
| SMC2 | Condensin | Smc2 | Cut14 | MIX-1 | DmSmc2 | CAP-E/SMC2 |
| SMC3 | Cohesin | Smc3 | Psm3 | SMC-3 | DmSmc3 | SMC3 |
| SMC4 | Condensin | Smc4 | Cut3 | SMC-4 | DmSmc4 | CAP-C/SMC4 |
| SMC5 | SMC5-6 | Smc5 | Smc5 | C27A2.1 | CG32438 | SMC5 |
| SMC6 | SMC5-6 | Smc6 | Smc6/Rad18 | C23H4.6, F54D5.14 | CG5524 | SMC6 |
| SMC1β | Cohesin (meiotic) | - | - | - | - | SMC1β |
| SMC4 variant | Dosage compensation complex | - | - | DPY-27 | - | - |
SMC proteins are conserved from bacteria to humans. [14] [15] Most bacteria have a single SMC protein in individual species that forms a homodimer. [16] [17] Recently SMC proteins have been shown to aid the daughter cells DNA at the origin of replication to guarantee proper segregation. In a subclass of Gram-negative bacteria, including Escherichia coli , a distantly related protein known as MukB plays an equivalent role. [18]
SMC proteins are 1,000-1,500 amino-acid long. They have a modular structure that is composed of the following domains:
SMC dimers form a V-shaped molecule with two long coiled-coil arms. [19] [20] To make such a unique structure, an SMC protomer is self-folded through anti-parallel coiled-coil interactions, forming a rod-shaped molecule. At one end of the molecule, the N-terminal and C-terminal domains form an ATP-binding domain. The other end is called a hinge domain. Two protomers then dimerize through their hinge domains and assemble a V-shaped dimer. [21] [22] The length of the coiled-coil arms is ~50 nm long. Such long "antiparallel" coiled coils are very rare and found only among SMC proteins (and their relatives such as Rad50). The ATP-binding domain of SMC proteins is structurally related to that of ABC transporters, a large family of transmembrane proteins that actively transport small molecules across cellular membranes. It is thought that the cycle of ATP binding and hydrolysis modulates the cycle of closing and opening of the V-shaped molecule. Still, the detailed mechanisms of action of SMC proteins remain to be determined.
The SMC proteins have the potential to form a larger ring-like structure. The ability to create different architectural arrangements allows for various regulations of functions. Some of the possible configurations are double rings, filaments, and rosettes. Double rings are 4 SMC proteins bound at the heads and hinge, forming a ring. Filaments are a chain of alternating SMCs. Rosettes are rose-like structures with terminal segments in the inner region and hinge in the outer region. [23]
The following human genes encode SMC proteins:
Condensins are large protein complexes that play a central role in chromosome assembly and segregation during mitosis and meiosis. Their subunits were originally identified as major components of mitotic chromosomes assembled in Xenopus egg extracts.
The spindle checkpoint, also known as the metaphase-to-anaphase transition, the spindle assembly checkpoint (SAC), the metaphase checkpoint, or the mitotic checkpoint, is a cell cycle checkpoint during mitosis or meiosis that prevents the separation of the duplicated chromosomes (anaphase) until each chromosome is properly attached to the spindle. To achieve proper segregation, the two kinetochores on the sister chromatids must be attached to opposite spindle poles. Only this pattern of attachment will ensure that each daughter cell receives one copy of the chromosome. The defining biochemical feature of this checkpoint is the stimulation of the anaphase-promoting complex by M-phase cyclin-CDK complexes, which in turn causes the proteolytic destruction of cyclins and proteins that hold the sister chromatids together.
Kim Ashley Nasmyth is an English geneticist, the Whitley Professor of Biochemistry at the University of Oxford, a Fellow of Trinity College, Oxford, former scientific director of the Research Institute of Molecular Pathology (IMP), and former head of the Department of Biochemistry, University of Oxford. He is best known for his work on the segregation of chromosomes during cell division.
Separase, also known as separin, is a cysteine protease responsible for triggering anaphase by hydrolysing cohesin, which is the protein responsible for binding sister chromatids during the early stage of anaphase. In humans, separin is encoded by the ESPL1 gene.
Cohesin is a protein complex that mediates sister chromatid cohesion, homologous recombination, and DNA looping. Cohesin is formed of SMC3, SMC1, SCC1 and SCC3. Cohesin holds sister chromatids together after DNA replication until anaphase when removal of cohesin leads to separation of sister chromatids. The complex forms a ring-like structure and it is believed that sister chromatids are held together by entrapment inside the cohesin ring. Cohesin is a member of the SMC family of protein complexes which includes Condensin, MukBEF and SMC-ScpAB.
Structural maintenance of chromosomes protein 1A (SMC1A) is a protein that in humans is encoded by the SMC1A gene. SMC1A is a subunit of the cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. In somatic cells, cohesin is formed of SMC1A, SMC3, RAD21 and either SA1 or SA2 whereas in meiosis, cohesin is formed of SMC3, SMC1B, REC8 and SA3.
Double-strand-break repair protein rad21 homolog is a protein that in humans is encoded by the RAD21 gene. RAD21, an essential gene, encodes a DNA double-strand break (DSB) repair protein that is evolutionarily conserved in all eukaryotes from budding yeast to humans. RAD21 protein is a structural component of the highly conserved cohesin complex consisting of RAD21, SMC1A, SMC3, and SCC3 [ STAG1 (SA1) and STAG2 (SA2) in multicellular organisms] proteins, involved in sister chromatid cohesion.
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 is formed of SMC3, SMC1, RAD21 and either SA1 or SA2. In humans, SMC3 is present in all cohesin complexes whereas there are multiple paralogs for the other subunits.
Wings apart-like protein homolog (WAPL) is a protein that in humans is encoded by the WAPAL gene. WAPL is a key regulator of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. Cohesin is formed of SMC3, SMC1, RAD21 and either SA1 or SA2. Cohesin has a ring-like arrangement and it is thought that it associates with the chromosome by entrapping it whether as a loop of DNA, a single strand or a pair of sister chromosomes. WAPL forms a complex with PDS5A or PDS5B and releases cohesin from DNA by opening the interface between SMC3 and RAD21.
Structural maintenance of chromosomes protein 4 (SMC-4) also known as chromosome-associated polypeptide C (CAP-C) or XCAP-C homolog is a protein that in humans is encoded by the SMC4 gene. SMC-4 is a core subunit of condensin I and II, large protein complexes involved in high order chromosome organization, including condensation and segregation. SMC-4 protein is commonly associated with the SMC-2 protein, another protein complex within the SMC protein family. SMC-4 dimerizes with SMC-2, creating the flexible and dynamic structure of the condensin holocomplex. An over-expression of the SMC-4 protein is shown to impact carcinogenesis.
Structural maintenance of chromosomes protein 5 is a protein encoded by the SMC5 gene in human.
Condensin-2 complex subunit D3 (CAP-D3) also known as non-SMC condensin II complex subunit D3 (NCAPD3) is a protein that, in humans, is encoded by the NCAPD3 gene. CAP-D3 is a subunit of condensin II, a large protein complex involved in chromosome condensation.
Condensin complex subunit 2 also known as chromosome-associated protein H (CAP-H) or non-SMC condensin I complex subunit H (NCAPH) is a protein that in humans is encoded by the NCAPH gene. CAP-H is a subunit of condensin I, a large protein complex involved in chromosome condensation
Condensin-2 complex subunit G2 (CAP-G2) also known as chromosome-associated protein G2 (CAP-G2) or leucine zipper protein 5 (LUZP5) is a protein that in humans is encoded by the NCAPG2 gene. CAP-G2 is a subunit of condensin II, a large protein complex involved in chromosome condensation. It interacts with PLK1 through its C-terminal region during mitosis
Structural maintenance of chromosomes protein 2 (SMC-2), also known as chromosome-associated protein E (CAP-E), is a protein that in humans is encoded by the SMC2 gene. SMC2 is part of the SMC protein family and is a core subunit of condensin I and II, large protein complexes involved in chromosome condensation, overall organization. Several studies have demonstrated the necessity of SMC2 for cell division and proliferation.
Sister chromatid cohesion refers to the process by which sister chromatids are paired and held together during certain phases of the cell cycle. Establishment of sister chromatid cohesion is the process by which chromatin-associated cohesin protein becomes competent to physically bind together the sister chromatids. In general, cohesion is established during S phase as DNA is replicated, and is lost when chromosomes segregate during mitosis and meiosis. Some studies have suggested that cohesion aids in aligning the kinetochores during mitosis by forcing the kinetochores to face opposite cell poles.
Condensin-2 complex subunit H2, also known as chromosome-associated protein H2 (CAP-H2) or non-SMC condensin II complex subunit H2 (NCAPH2), is a protein that in humans is encoded by the NCAPH2 gene. CAP-H2 is a subunit of condensin II, a large protein complex involved in chromosome condensation.
Structural maintenance of chromosomes protein 1B (SMC-1B) is a protein that in humans is encoded by the SMC1B gene. SMC proteins engage in chromosome organization and can be broken into 3 groups based on function which are cohesins, condensins, and DNA repair.SMC-1B belongs to a family of proteins required for chromatid cohesion and DNA recombination during meiosis and mitosis. SMC1ß protein appears to participate with other cohesins REC8, STAG3 and SMC3 in sister-chromatid cohesion throughout the whole meiotic process in human oocytes.
Frank Uhlmann FRS is a group leader at the Francis Crick Institute in London.
Xenopus egg extract is a lysate that is prepared by crushing the eggs of the African clawed frog Xenopus laevis. It offers a powerful cell-free system for studying various cell biological processes, including cell cycle progression, nuclear transport, DNA replication and chromosome segregation. It is also called Xenopus egg cell-free system or Xenopus egg cell-free extract.
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