Centromere Protein A (CENP-A) is a specialized protein found in the cells of most living organisms, including humans. It is a variant of histone H3, a common protein that helps organize DNA into nucleosomes. CENP-A plays a distinct role in managing genetic material. This protein contributes to fundamental cellular processes by ensuring the proper handling of chromosomes.
Location and Structure
CENP-A is found specifically at the centromere, a constricted region on each chromosome. Unlike other histone proteins broadly distributed across the genome, CENP-A’s presence defines the centromere’s identity. This specialized protein replaces conventional histone H3 within nucleosomes at these centromeric regions.
The structure of CENP-A includes a histone fold domain, similar to histone H3, but also distinct N-terminal and C-terminal tails. These structural differences allow CENP-A to establish a unique chromatin environment at the centromere. This modified nucleosome structure, containing CENP-A instead of H3, alters how DNA is wrapped. This specialized centromeric chromatin provides the foundation for the assembly of other proteins involved in cell division.
Core Function in Cell Division
CENP-A’s primary function is creating a platform for the kinetochore during cell division. The kinetochore is a complex protein structure that assembles directly on the CENP-A-containing chromatin at the centromere. CENP-A recruits other centromere proteins like CENP-C and CENP-N, which then recruit additional kinetochore proteins.
Once assembled, the kinetochore acts as the attachment point for microtubules, components of the spindle fibers that extend from the cell’s poles during mitosis and meiosis. These microtubules attach to the kinetochore, pulling sister chromatids (identical copies of chromosomes) apart. This ensures that each new daughter cell receives a complete and accurate set of chromosomes. Maintaining CENP-A at the centromere helps preserve its position and function across cell generations.
Role in Genomic Stability
Beyond its direct involvement in cell division, CENP-A maintains genomic stability. Its accurate function during chromosome segregation helps prevent aneuploidy, a condition characterized by an abnormal number of chromosomes in a cell. Aneuploidy can arise from errors in chromosome separation, where daughter cells end up with too many or too few chromosomes.
CENP-A also contributes to genomic stability by facilitating the proper replication of centromeric DNA repeats. It helps suppress the formation of R-loops, structures where RNA binds to DNA, which can interfere with DNA replication and lead to breaks. Impaired centromeric replication due to CENP-A depletion can lead to fragile sites and chromosome bridges during cell division, increasing the risk of chromosome breakage. This function ensures the integrity of these repetitive regions, which are otherwise prone to instability.
CENP-A and Disease
Dysregulation of CENP-A can contribute to various human diseases, particularly cancer. Overexpression or mislocalization of CENP-A has been observed in numerous cancer types, including breast, lung, colon, liver, ovarian, and gastric cancers. Elevated CENP-A expression is a common feature in human cancers, correlating with poor prognosis and increased metastatic potential.
When CENP-A is overexpressed, it can be deposited in non-centromeric regions of chromosomes, leading to the formation of ectopic kinetochores or weakening of native kinetochores. This mislocalization contributes to chromosomal instability, characterized by errors in chromosome segregation, such as lagging chromosomes and the formation of micronuclei. These defects can result in aneuploidy and genomic heterogeneity, promoting tumor progression and drug resistance. Targeting CENP-A has been explored as a potential strategy for cancer therapy, as its depletion in cancer cells can suppress cell growth, block cell cycle progression, and promote apoptosis.