Centromere protein L is a protein that in humans is encoded by the CENPLgene known for its role in forming the centromere and building a functional kinetochore during cell division.[5][6][7] CENPL acts as part of the CENP-L/N complex and also contributes to larger centromeric groups such as CENPA-CAD and CENP-H/I/K/L/M subcomplexes, which belong to the constitutive centromere-associated network (CCAN). These proteins work together to recognize CENPA-containing nucleosomes and help establish the site where the kinetochore will assemble. CENPL is important for guiding the early steps of kinetochore formation, maintaining centromere structure, and supporting accurate chromosome segregation during mitosis.
CENPL was identified as part of a broader effort to classify the proteins associated with CENPA, CENPH, and CENPI in vertebrate cells. These studies led to the discovery of several new CENP proteins including CENPL and CENPN, which were grouped with other newly described proteins into what is now known as CCAN.[8] As these CCAN components were examined more closely, biochemical and structural analyses showed that CENP-L forms a stable complex with CENP-N, creating the CENP-L/N complex, one of the four major CCAN subcomplexes.[8][9]
Protein Structure
CENPL is an inner-kinetochore protein whose structural properties are defined through its association with CENPN as part of the CENP-L/N complex. Structural studies in other organisms have shown that CENPL and CENPN form a stable heterodimer, and this overall arrangement is conserved across species.[8] In human cells, biochemical work indicates that CENPL binds to the C-terminal region of CENPN to form the complete complex.[9]
Although CENPL does not possess known catalytic domains, its structural role within the CENP-L/N complex helps support the organization of the inner kinetochore. Through its association with CENPN and its place within the CCAN, CENPL contributes to maintaining the interactions needed for proper inner-kinetochore assembly.[9]
Evolution and Conservation
CENPL is part of a group of centromere associated proteins that show evidence of evolutionary conservation across eukaryotic organisms. Studies of kinetochore organization have shown that several CCAN components, including the CENP-L/N complex, are present from budding yeast to vertebrates even though their exact amino acid sequences differ among species.[8] Structural work in budding yeast has been helpful for understanding this conservation, since the crystallized yeast CENP-L/N complex forms a heterodimer that closely resembles the predicted arrangement of the human proteins. Although centromeres differ widely in size and DNA sequence among species, the relationships among CENP-L/N, CENP-C, and other CCAN components seem to follow a stable and recurring pattern.[9] This consistency reinforces the idea that the inner kinetochore is built on a conserved structural framework and highlights the importance of CENPL in maintaining a kinetochore capable of supporting accurate chromosome segregation.
CENP-L/N Complex
The CENP-L/N complex is formed when CENPL associates with its binding partner CENPN, creating a stable heterodimer that acts as one of the core subcomplexes within the CCAN. In this complex, CENPN directly recognizes CENPA-containing nucleosomes through its interaction with the CENPA centromere domain, while CENPL binds the C terminal region of CENPN to complete the heterodimer. [9] As part of the CCAN, the CENP-L/N complex helps maintain the organization of the inner kinetochore and supports the centromere localization of other CCAN components. When CENPN is disrupted and the complex cannot assemble properly, several proteins such as CENPI and CENPT lose their normal localization at the centromere, showing that the CENP-L/N complex plays a key role in stabilizing CCAN structure and supporting accurate kinetochore assembly.[9]
CENPL in Early Centromere Assembly
During early centromere assembly, the CENP-L/N complex helps establish the initial connections between CENPA chromatin and the CCAN network. Studies show that when this complex is disrupted, several CCAN components fail to remain at centromeres, indicating that CENPL contributes to forming the early inner-kinetochore environment needed before outer kinetochore structures assemble.[9] This role places CENPL within the set of CCAN subunits that support the early organization of centromeric chromatin as the kinetochore begins to form.[8]
Expression and localization
CENPL is expressed in human cells that divide often, which matches its role in helping organize the centromere and build the kinetochore. According to gene databases, CENPL shows strongest functional relevance in tissues with high cell-cycle activity, since accurate chromosome separation depends on having the right centromere components in place.[10] Because CENPL works closely with CENPA-containing chromatin, its presence at the centromere is tied to the early steps of kinetochore assembly.
Research on kinetochore organization shows that CENPL stays associated with centromeric regions throughout the entire cell cycle, but its role becomes most important as cells enter mitosis.[8] During early mitosis, CENPA nucleosomes begin recruiting CCAN proteins, including the CENP-L/N complex, which depends on CENPL to help secure their position at the centromere.[9] Having CENPL already in place before microtubules attach helps create a stable environment for proper chromosome alignment and segregation.
Functional studies also show that CENPL needs to be correctly localized for the centromere to form normally. When CENPL levels are reduced, other CCAN proteins do not load efficiently, weakening the inner kinetochore and delaying chromosome alignment during mitosis.[11] These findings support the idea that CENPL’s expression and location at the centromere are tightly linked to its role in maintaining accurate cell division.
Function
CENPL works as part of the CENP-L/N complex, where it helps keep the inner kinetochore organized and stable. When researchers disrupted this complex, several other CCAN proteins csuch as CENPI and CENPT no longer stayed at the centromere the way they normally do. This showed that CENPL is important for holding together the network of proteins that make up the inner kinetochore.[9]
CENPL also interacts with CENPC and the CENP-H/I/K/M group, and those connections seem to help link CENPA chromatin to the rest of the kinetochore structure. This whole set of proteins as forming a larger platform that the outer kinetochore builds on, so CENPL ends up being part of the framework that lets the kinetochore form correctly at the centromere.[8]
Kinetochore-Microtubule Attachment
CENPL does not bind microtubules directly, but it still influences how kinetochore–microtubule attachments form by helping maintain the organization of the inner kinetochore. When the CENP-L/N complex is disrupted, several CCAN proteins that normally contribute to building the outer kinetochore do not remain properly localized at the centromere, which weakens attachments.[9]
Studies on kinetochore mechanics also show that reducing CCAN components leads to less stable microtubule attachments. Cells with disrupted CCAN function display irregular chromosome movements and alignment defects during mitosis, indicating problems with the stability of kinetochore–microtubule interactions.[11] Because many of these CCAN proteins depend on the CENP-L/N complex for their centromere localization, CENPL plays an indirect but important role in supporting proper microtubule attachment and accurate chromosome segregation.
Genomic Stability
CENPL contributes to maintaining conditions required for accurate chromosome segregation through its role in the CENP-L/N complex and its association with pathways involved in cell-cycle progression. Disruption of CENPN, and therefore the CENP-L/N complex, leads to weakened inner-kinetochore organization and chromosome alignment defects during mitosis, conditions that can challenge genomic stability.[9] Recent cancer studies also show that high CENPL expression is closely linked to cell-cycle and chromosome-segregation pathways in breast cancer, including processes such as nuclear division and organelle fission.[12] Because proper regulation of these pathways is essential for stable chromosome inheritance, alterations in CENPL expression may influence cellular environments that affect genome maintenance.
Cell Cycle Regulation
CENPL is closely linked to pathways that control the cell cycle and changes in its expression can influence how quickly cells progress through stages of division. Genome wide expression analyses in breast cancer have shown that high CENPL expression is strongly associated with gene sets involved in nuclear division, organelle fission, chromosome segregation, and other mitotic processes.[12] These enrichment results suggest that CENPL is part of a broader regulatory environment that supports rapid cell cycle progression in dividing cells.
Additional transcriptomic studies have identified CENPL as one of several upregulated hub genes associated with DNA replication and cell-cycle activation in tumor tissues. High expression of CENPL was consistently enriched in pathways related to cell-cycle control across multiple breast cancer datasets, including “cell cycle” and “DNA replication” pathways identified through GSEA and GSVA analyses.[13] Experimental evidence further supports a functional role for CENPL in regulating cell-cycle dynamics. In breast cancer cell lines, CENPL knockdown significantly reduced cell proliferation rates and colony formation ability, indicating that CENPL helps maintain the conditions necessary for growth.[12] By contributing to pathways involved in nuclear division and cell-cycle progression, CENPL may help coordinate the timing and efficiency of mitotic events in rapidly dividing cells.
Clinical Significance
Patterns of CENPL expression across cancer studies show that this gene is often upregulated in tumors, especially in cancers with high rates of cell division. Analyses from breast cancer datasets show that CENPL correlates with genes involved in nuclear division, DNA replication, and chromosome segregation, indicating that its expression tends to rise in cells actively progressing through the cell cycle.[12] In some cases, increased expression may be influenced by changes in gene regulation, including copy number gains or altered DNA methylation patternswhich can make the gene more transcriptionally active in tumor environments.[13] Although the exact regulatory mechanisms still need further investigation, these observations suggest that CENPL expression responds to broader shifts in cell-cycle activity and tumor growth signals. In breast cancer, higher levels of CENPL expression are linked to poorer relapse-free and distant metastasis-free survival, implying that tumors expressing more CENPL may behave more aggressively[12]. Large-scale analyses also identify CENPL as one of several hub genes with possible diagnostic value, since its expression patterns can help distinguish tumor samples from normal tissue with relatively high accuracy.[13] Elevated CENPL expression is also seen in liver, lung, ovarian, and several gastrointestinal cancers, and experimental work in hepatocellular carcinoma shows that reducing CENPL disrupts proliferation and affects MEK1/2–ERK1/2 signaling, which supports tumor cell survival.[13] Overall current evidence suggests that CENPL may play a broader role in supporting rapid tumor growth across different cancer systems, although research outside breast cancer and HCC remains limited.
Cancer
CENPL plays a role in cancer because of its involvement in cell division and chromosome segregation. Since CENPL helps form the early structure of the kinetochore and supports normal mitosis, changes in its expression may influence how quickly cells progress through the cell cycle and how accurately chromosomes are separated during division.[12]
A study of hepatocellular carcinoma (HCC) found that higher CENPL expression directly increased cancer cell proliferation and helped push cells through the cell cycle at a faster rate. Reducing CENPL expression caused the opposite effect, leading to slower growth, increased apoptosis, and changes in cellular metabolism. CENPL activates the MEK1/2–ERK1/2 signaling pathway, which is involved in supporting tumor cell survival and promoting cancer progression. It is reported that CENPL influences glycolytic activity in HCC cells, suggesting that it helps tumors meet the metabolic demands of rapid cell division.[13]
Breast cancer
Research on breast cancer has also shown that CENPL may influence tumor behavior through its role in cell division. In a 2023 study, higher CENPL expression was associated with increased breast cancer cell proliferation and with immune-infiltration patterns that often appear in aggressive tumors. Because CENPL is required for normal mitosis and works with CENPN to locate CENPA nucleosomes, the authors suggested that elevated expression may give tumor cells an advantage by supporting the high rate of division needed for tumor growth. The study also reported that CENPL expression correlates with several immune-related markers, indicating that CENPL may play a role in shaping the tumor microenvironment as these cells expand.[12] While more research is needed, these findings highlight CENPL as a potential contributor to breast cancer progression and an emerging point of interest for understanding how chromosomal stability and cell-cycle control influence tumor development.[12]
↑"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑Okada M, Cheeseman IM, Hori T, Okawa K, McLeod IX, Yates JR, etal. (May 2006). "The CENP-H-I complex is required for the efficient incorporation of newly synthesized CENP-A into centromeres". Nature Cell Biology. 8 (5): 446–457. doi:10.1038/ncb1396. PMID16622420. S2CID26974412.
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