Actin Filaments in Mitosis: Key Functions and Impact
Explore the role of actin filaments in mitosis, from structural dynamics to coordination with microtubules, and their impact on genome stability.
Actin filaments, a key component of the cytoskeleton, play a crucial role in mitosis beyond their well-known functions in cell shape and motility. While microtubules are often emphasized in chromosome segregation, actin dynamics contribute to spindle positioning, force generation, and cytokinesis. Understanding how actin filaments coordinate with other cellular structures during mitosis provides insight into mechanisms that maintain genomic integrity and prevent errors leading to diseases like cancer.
Structural Rearrangements in Prophase
As a cell enters prophase, actin filaments reorganize to support mitotic progression. Unlike their interphase role in maintaining cell shape and adhesion, these filaments shift in distribution and dynamics. A key change is the disassembly of actin-rich cortical structures, allowing increased cellular rounding necessary for spindle formation. This transition is mediated by actin-binding proteins like cofilin and gelsolin, which sever and depolymerize filaments, reducing cortical rigidity and facilitating cytoskeletal remodeling.
Actin polymerization near the nuclear periphery also contributes to nuclear envelope breakdown, generating forces that assist in lamin disassembly. Myosin II exerts contractile forces that fragment the nuclear envelope, ensuring efficient chromosome access to the mitotic spindle. Disruptions in this mechanism can delay nuclear envelope breakdown, leading to mitotic errors and genomic instability.
Additionally, actin filaments influence centrosome positioning and spindle assembly. During prophase, centrosomes separate with support from actin-microtubule interactions. The Arp2/3 complex facilitates branched actin networks that aid centrosome migration. Impairing actin polymerization at this stage can misalign centrosomes, compromising spindle bipolarity and chromosome segregation.
Coordination in Metaphase and Anaphase
During metaphase, actin filaments help maintain spindle architecture and chromosome alignment, reinforcing kinetochore-microtubule attachments. Myosin II generates forces that fine-tune chromosome positioning, preventing misalignment that could lead to segregation defects. Disruptions in actin organization at this stage have been linked to lagging chromosomes and aneuploidy.
In anaphase, actin filaments support spindle elongation and cortical force generation, ensuring accurate chromosome distribution. Actin-rich structures at the cortex, regulated by formins and the Arp2/3 complex, anchor spindle poles and direct chromosome movement. Perturbing these cortical actin structures can lead to asymmetric spindle positioning and unequal chromosome segregation.
Actin filaments also contribute to furrow ingression during late anaphase, preparing the cell for cytokinesis. Myosin II-driven contractions generate inward forces that initiate cleavage furrow constriction. This actin-dependent mechanism minimizes chromosomal bridges or incomplete separation, reducing genomic instability.
Cooperative Role With Microtubules
The interplay between actin filaments and microtubules ensures accurate chromosome segregation and spindle function. While microtubules form the mitotic spindle, actin filaments provide structural support for spindle positioning and stability. Crosslinking proteins like spectraplakins bridge actin and microtubule networks, coordinating their activities. Cells lacking functional spectraplakins exhibit spindle misalignment and inefficient chromosome congression.
Actin filaments regulate microtubule dynamics by modulating polymerization rates. Formins stabilize microtubule plus-ends, while actin-associated motor proteins like dynein and myosin influence spindle orientation by tethering microtubules to cortical actin structures. This interaction is essential in asymmetrically dividing cells, where precise spindle positioning determines daughter cell fate.
Actin filaments also regulate microtubule-associated signaling pathways that govern mitotic progression. Rho-family GTPases, including RhoA and Cdc42, coordinate actin and microtubule remodeling by modulating effectors such as mDia and ROCK kinases. Disrupting these signaling pathways leads to spindle instability and prolonged mitotic arrest, emphasizing actin’s regulatory role in microtubule function.
Regulators of Filament Organization
The dynamic behavior of actin filaments during mitosis is controlled by regulatory proteins that govern their assembly, disassembly, and spatial distribution. Actin nucleation factors like the Arp2/3 complex and formins shape filament architecture, promoting either branched or linear polymerization. The Arp2/3 complex stabilizes spindle structures, while formins drive unbranched filament elongation, supporting cortical tension and cleavage furrow formation.
Post-translational modifications of actin-regulatory proteins refine filament dynamics in a cell cycle-dependent manner. Phosphorylation of cofilin, an actin-severing protein, regulates filament turnover. During early mitosis, cofilin is phosphorylated to maintain actin stability, then dephosphorylated near cytokinesis to facilitate contractile ring formation. Rho-family GTPases, including RhoA and Rac1, further modulate actin reorganization by influencing downstream effectors like mDia and ROCK kinases, ensuring actin filaments provide necessary mechanical support for chromosome segregation.
Cytokinesis and Contractile Ring Formation
Actin filaments play a central role in cytokinesis, physically separating the cytoplasm into two daughter cells. This process is driven by the contractile ring, an actin-myosin structure that assembles at the equatorial cortex. Signals from the central spindle and astral microtubules regulate its positioning. RhoA activates formins and myosin II, promoting actin polymerization and contractile forces. Disruptions in RhoA signaling can lead to cytokinesis failure, resulting in binucleated cells linked to tumorigenesis.
Once formed, the contractile ring constricts through coordinated actin-myosin activity. Severing proteins like cofilin and gelsolin facilitate filament disassembly, allowing progressive ring tightening. Vesicle trafficking pathways contribute membrane components to the cleavage furrow, supporting final abscission. Defects in actin remodeling at this stage can lead to chromatin bridges and DNA damage, emphasizing precise actin regulation for successful cytokinesis.
Implications for Genome Stability
Actin filaments contribute to genome stability by ensuring spindle positioning, chromosome segregation, and cytokinesis occur without errors that could lead to aneuploidy or DNA damage. Proper actin dynamics support centrosome function, preventing spindle defects that cause chromosomal instability. Centrosome mispositioning, often linked to defective actin regulation, has been implicated in tumor progression.
Actin filaments also help prevent DNA damage during mitotic exit. Incomplete cytokinesis or contractile ring defects can lead to micronuclei formation, which increases DNA fragmentation and replication stress. Additionally, actin-mediated nuclear repositioning ensures daughter nuclei remain properly oriented, reducing mechanical stress-induced DNA damage. Studies have linked actin cytoskeletal defects to various cancers, underscoring the importance of actin regulation in maintaining genomic stability.