Sister Chromatid: Key Role in Cell Division and DNA Repair

Cells rely on precise mechanisms to ensure genetic material is accurately copied and distributed. Sister chromatids, identical copies of a chromosome joined after DNA replication, play a crucial role in this process. Beyond duplication, they contribute to genetic stability and adaptability.

Understanding their function sheds light on key biological processes such as cell division, genetic variation, and DNA repair.

Mitosis And Sister Chromatid Structure

Mitosis ensures genetic material is evenly distributed between two daughter cells, a process dependent on sister chromatids. These identical DNA copies form during the S phase of the cell cycle when a chromosome is duplicated, resulting in two chromatids connected at the centromere. This attachment is reinforced by cohesin, a protein complex that maintains alignment until separation is required. Errors in chromatid formation or segregation can lead to aneuploidy, a condition linked to developmental disorders and cancers.

As mitosis progresses, sister chromatids undergo orchestrated movements to ensure equal genetic distribution. During prophase, chromatin condenses into distinct chromosomes, making sister chromatids visible. The nuclear envelope disintegrates, allowing spindle fibers to interact with kinetochores—protein structures at the centromere that serve as attachment points for microtubules. These microtubules align chromatids along the metaphase plate, with the spindle assembly checkpoint ensuring proper attachment before anaphase proceeds.

Once alignment is confirmed, the anaphase-promoting complex (APC/C) triggers cohesin degradation, allowing sister chromatids to separate. They move toward opposite poles of the cell, guided by microtubule shortening. Accurate segregation is critical, as errors can lead to daughter cells with missing or extra chromosomes, a hallmark of many malignancies. By telophase, chromatids—now individual chromosomes—reach their respective poles, and the nuclear envelope reforms, completing division.

Cohesion And Separation Mechanics

Sister chromatids remain paired until separation is necessary, a process controlled by the cohesin complex, a ring-shaped multiprotein structure. Cohesin is loaded onto chromatin during the S phase, ensuring newly replicated DNA strands stay together. This linkage facilitates chromosome alignment and prevents premature separation. The cohesin subunits SMC1, SMC3, RAD21, and SCC3 regulate chromatid cohesion, with SMC3 acetylation by ESCO1 and ESCO2 reinforcing cohesin’s grip.

As cells enter mitosis, cohesin modulation allows chromosomal movement while maintaining genomic integrity. Early in prophase, kinases like PLK1 and Aurora B phosphorylate cohesin, releasing it from chromosome arms while preserving centromeric cohesion. This configuration ensures proper kinetochore-microtubule interactions. The spindle assembly checkpoint delays anaphase if improper attachments occur, preventing missegregation.

Anaphase begins when separase cleaves the cohesin subunit RAD21, dismantling the last links between sister chromatids. This event, regulated by securin degradation via APC/C, ensures synchronized segregation. Microtubule depolymerization propels chromatids apart, aided by motor proteins such as dynein and kinesin.

Role In Meiosis And Gamete Formation

Sister chromatids are central to meiosis, the specialized division producing gametes with half the chromosome number of somatic cells. Unlike mitosis, which creates identical daughter cells, meiosis introduces genetic variation through two sequential divisions. In meiosis I, homologous chromosomes—each consisting of two sister chromatids—pair and undergo recombination, enhancing genetic diversity. Crossing over occurs at chiasmata, where homologs remain linked until separation. Cohesion ensures proper alignment and prevents premature separation, reducing the risk of aneuploidy.

Following homologous chromosome separation in meiosis I, meiosis II resembles mitosis but occurs without DNA replication. Sister chromatids remain attached at their centromeres while spindle fibers connect to kinetochores. Shugoshin proteins protect centromeric cohesin from premature cleavage until meiosis II, when separase degrades cohesin, allowing chromatid separation. Errors in this process can result in conditions such as trisomy 21, where improper segregation leads to an extra chromosome in the gamete.

Sister Chromatid Exchanges

Sister chromatid exchanges (SCEs) involve the swapping of identical DNA segments between sister chromatids during replication. While these exchanges do not alter genetic content, frequent occurrences suggest genomic instability linked to DNA damage or defective repair mechanisms. SCEs are detected using bromodeoxyuridine (BrdU) labeling, which differentiates newly synthesized DNA strands from original templates. High SCE frequencies are observed in cells exposed to mutagenic agents such as ionizing radiation and certain chemotherapy drugs, making them a biomarker for genotoxic stress.

SCEs are closely associated with homologous recombination, a repair pathway for DNA double-strand breaks. Proteins such as RAD51 and BRCA2 facilitate accurate genetic exchange between sister chromatids, ensuring replication fidelity. However, disruptions in these pathways can lead to excessive SCEs, as seen in Bloom syndrome, a genetic disorder caused by BLM helicase mutations. Individuals with this condition exhibit a tenfold increase in SCE frequency, predisposing them to chromosomal aberrations and cancer.

Chromosomal Abnormalities Involving Sister Chromatids

Defects in chromatid cohesion, separation, or repair can lead to chromosomal abnormalities that disrupt normal function. One severe outcome is aneuploidy, where cells inherit an incorrect chromosome number due to improper segregation. Conditions such as Down syndrome (trisomy 21) result from chromatid missegregation during gamete formation. Similar errors contribute to Turner syndrome (monosomy X) and Klinefelter syndrome (XXY), often linked to cohesin dysfunction or spindle checkpoint failure.

Beyond aneuploidy, structural abnormalities involving sister chromatids can manifest as deletions, duplications, or translocations. Fragile X syndrome stems from an unstable repeat expansion on the X chromosome that disrupts chromatid integrity. In cancers like chronic myeloid leukemia, translocations between chromatids or homologous chromosomes create fusion genes that drive uncontrolled proliferation. Chromosomal bridges—where sister chromatids fail to separate—can lead to genome instability, increasing tumorigenesis risk. Defects in topoisomerases and helicases further exacerbate these abnormalities, highlighting the need for precise chromatid management.

Role Of Sister Chromatids In DNA Repair

Sister chromatids serve as templates for DNA repair, particularly in response to double-strand breaks (DSBs), the most severe form of DNA damage. Cells use homologous recombination (HR) to restore lost or damaged sequences, relying on the intact sister chromatid as a blueprint. This process is active during the S and G2 phases when sister chromatids are available. Proteins such as RAD51, BRCA1, and BRCA2 facilitate strand invasion and template-based synthesis, ensuring accurate repair. Mutations in these pathways, particularly BRCA defects, significantly increase breast and ovarian cancer risk.

Beyond DSB repair, sister chromatids help resolve stalled replication forks, which arise from DNA damage or replication stress. The Fanconi anemia pathway, involving proteins such as FANCD2 and FANCI, stabilizes replication machinery and promotes template switching between chromatids. Failure to resolve stalled forks leads to replication-associated DSBs, increasing the risk of chromosomal rearrangements or cell death. Sister chromatids also aid in telomere maintenance, preventing chromosome ends from being misrecognized as DNA breaks. This function is especially critical in stem cells and rapidly dividing tissues, where telomere integrity supports cellular longevity and genomic stability.