Microscopic cell division with clockwork gears representing ESCO2 timing.

Decoding Cell Division: How ESCO2's Timing Impacts Our Health

Samir D’Costa in Health & Wellness August 2025 • 4 min read.

"Unraveling the mysteries of ESCO2 degradation and its critical role in preventing genetic errors during cell division."

Cell division, a fundamental process of life, ensures the faithful transmission of genetic information from one generation of cells to the next. This intricate dance involves precise choreography of numerous proteins, one of which, ESCO2, plays a pivotal role. Recent research published in Current Biology sheds light on how the timing of ESCO2 degradation is meticulously regulated, impacting the accuracy of cell division and potentially preventing developmental disorders.

Sister chromatid cohesion, the process of holding duplicated chromosomes together until the appropriate moment of separation, is crucial for accurate chromosome segregation. This cohesion is mediated by a ring-like protein complex called cohesin, whose proper functioning depends on the acetylation of its SMC3 subunit. ESCO1 and ESCO2, two acetyltransferases, are responsible for this crucial modification.

While ESCO1 is present throughout the cell cycle, ESCO2 appears specifically during the S phase, the period of DNA replication, and is then degraded. The Current Biology article delves into the mechanisms that govern ESCO2's rise and fall, revealing the involvement of the MCM complex, the CUL4-DDB1-VPRBP complex, and the anaphase-promoting complex (APC).

Why is ESCO2's precise timing so critical for healthy development?

Microscopic cell division with clockwork gears representing ESCO2 timing.

The research highlights that ESCO2, unlike ESCO1, directly interacts with the MCM complex, a crucial component of the DNA replication machinery. This interaction ensures that ESCO2 is recruited to the correct locations on the chromosomes during S phase, precisely where and when cohesion needs to be established.

The MCM complex also plays a protective role, shielding ESCO2 from premature degradation by the proteasome, a cellular machine that breaks down proteins. This protection ensures that ESCO2 can fulfill its function of acetylating cohesin and establishing proper sister chromatid cohesion during DNA replication.

ESCO2 and MCM Complex: ESCO2 physically interacts with the MCM complex on chromatin, ensuring its precise location during DNA replication.
MCM Complex Protection: The MCM complex protects ESCO2 from proteasomal degradation during the S phase, allowing it to function properly.
CUL4-DDB1-VPRBP Interaction: The CUL4-DDB1-VPRBP complex interacts with ESCO2 in the late S/G2 phase, marking it for degradation after DNA replication.
APC Involvement: The CUL4-DDB1-VPRBP complex, along with APC, promotes ESCO2 degradation, preventing cohesion errors.

Later in the cell cycle, particularly in the late S and G2 phases, the CUL4-DDB1-VPRBP complex steps in. This complex, along with the APC, targets ESCO2 for degradation. This degradation is essential to prevent ESCO2 from continuing to acetylate cohesin after DNA replication is complete, which could lead to problems during mitosis, the actual process of cell division.

Why does ESCO2 need to be removed at the right time?

The findings suggest that precise timing of ESCO2 is crucial for preventing errors in chromosome segregation. By ensuring ESCO2 is active only during S phase and then degraded, the cell avoids the creation of excessive or misplaced cohesion, which can lead to aneuploidy (an abnormal number of chromosomes) and developmental abnormalities such as Roberts syndrome.

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Everything You Need To Know

What is the role of ESCO2 in cell division?

ESCO2 is an acetyltransferase protein that plays a crucial role in accurate cell division. It functions by acetylating the SMC3 subunit of the cohesin complex. This acetylation is essential for establishing sister chromatid cohesion, which holds duplicated chromosomes together until they are ready to separate during mitosis. The precise timing and activity of ESCO2, specifically during the S phase of the cell cycle, is critical for its function in ensuring proper chromosome segregation.

How does the MCM complex influence ESCO2 function?

The MCM complex plays a dual role in regulating ESCO2. First, ESCO2 physically interacts with the MCM complex, which ensures it is recruited to the correct locations on the chromosomes during the S phase, where and when cohesion needs to be established. Second, the MCM complex protects ESCO2 from premature degradation by the proteasome. This protection allows ESCO2 to function properly and acetylate cohesin, which is critical for sister chromatid cohesion during DNA replication. This interaction is a key mechanism in the precise timing of ESCO2's activity.

What happens to ESCO2 after DNA replication, and why is this important?

After DNA replication, specifically in the late S and G2 phases, ESCO2 needs to be degraded. The CUL4-DDB1-VPRBP complex interacts with ESCO2 and, along with the anaphase-promoting complex (APC), targets it for degradation. This is crucial because it prevents ESCO2 from continuing to acetylate cohesin after DNA replication is complete. If ESCO2 remained active, it could lead to excessive or misplaced cohesion, resulting in errors during mitosis. These errors can cause an abnormal number of chromosomes (aneuploidy) and potentially cause developmental abnormalities, such as Roberts syndrome.

What is the difference between ESCO1 and ESCO2?

ESCO1 and ESCO2 are both acetyltransferases involved in the acetylation of the SMC3 subunit of the cohesin complex, which is crucial for sister chromatid cohesion. However, ESCO1 is present throughout the cell cycle, while ESCO2 has a more specific role, appearing primarily during the S phase (DNA replication). The precise timing of ESCO2's activity is regulated by its interaction with the MCM complex during the S phase and its subsequent degradation, primarily by the CUL4-DDB1-VPRBP complex and APC. The difference in their timing and regulation highlights the importance of ESCO2's precise control to ensure proper cell division.

How does the timing of ESCO2 degradation impact health?

The precise timing of ESCO2 degradation is crucial for preventing errors in chromosome segregation, which directly impacts health. If ESCO2 is not degraded at the correct time, it can lead to excessive or misplaced cohesion between sister chromatids. This, in turn, can cause aneuploidy, which is an abnormal number of chromosomes. Aneuploidy can lead to developmental abnormalities and disorders, such as Roberts syndrome. Therefore, the proper regulation of ESCO2's rise and fall, orchestrated by the MCM complex, CUL4-DDB1-VPRBP complex, and APC, is vital for maintaining genomic stability and preventing health issues.