# The Less Known Cyclins--Uncovered
## 9 Cyclin L  
Cyclin L occurs in two forms: cyclin L1 encoded by the CCNL1 gene located on human chromosome 3 at position q25.31 and cyclin L2 encoded by the CCNL2 gene located on human chromosome 1 at position p36.33 [75]. Cyclin L is the first example of cyclin, which on the N-terminal domain contains a cyclin box, while on the C-terminal domain, the domain rich in alternating arginine and serine residues (RS domain), which is characteristic for serine and arginine-rich (SR) proteins. The RS domain mainly participates in RNA splicing, processing and transport. In terms of the structure, cyclin L is most similar to cyclin K [76; 77]. Human cyclins L1 and L2 have a different level of expression in various normal cells and tissues, and in tumor cells. Both forms are located in the cell nucleus [78]. Cyclin L binds and activates Cdk11, more specifically its isoform p110. Moreover, L1 and L2 cyclins may be divided into two groups. The first is the longer isoforms of L-\(\alpha\) cyclin containing the cyclin box on the N-terminal domain, and the RS domain at the C-terminus, while shorter L-\(\beta\) cyclin isoforms have only the cyclin domain [75; 78]. In normal cells, human L-\(\alpha\) cyclin is involved in the regulation of pre-mRNA splicing. The L-\(\alpha\) cyclin through the RS domain is involved in the splicing of the \(\beta\)-globin pre-mRNA and the E1A reporter gene. [PERSON] et al., 2008 [75] using the dual reporter system, showed that cyclin L1/2\(\alpha\) and \(\beta\) contribute to the growth of constitutive splicing, whereas the complex of cyclin L and Cdk11p110 WT intensified splicing even further. Using the second E1A minigene construct, which generates pre-mRNA, the authors demonstrated that Cdk11 p110 complexes with cyclin L1\(\alpha\), L2\(\alpha\) and L2\(\beta\) influence the choice of an alternative splicing site [75; 79]. The studies indicate the overexpression of cyclin L in head and neck cancers [79; 80; 81]. [PERSON] et al., 2002 [80] in their research used several cell lines: CAL 27 (squamous cell carcinoma  
Figure 3: During the replication stress, the cyclin dependent kinase 9 (Cdk9) accumulates on chromatin and reduces the amount of single-strand breaks. Cdk9 in complex with cyclin K interacts with ataxia telangiectasia and Rad3-related protein (ATR) and other damage response proteins and provides genome stability. In the presence of DNA damage, cyclin K/Cdk12/13 complexes induces the expression of DNA damage response genes. of the tongue), FaDu (lower throat cancer) and CAL 33 (squamous cell carcinoma of the tongue). They showed that in all three types of cancer only cyclin L gene is overexpressed. They concluded that the level of cyclin L is elevated in differentiated primary tumors, resulting in an increase in the number of proliferating cells [80]. [PERSON] et al., 2005 [81] studied a collection of 280 cases of squamous cell carcinoma of the head and neck (HNSCC), i.e., squamous carcinoma of the mouth (OSCC), squamous cell carcinoma of the throat (PSCC) and squamous cell carcinoma of the larynx (LSCC), in search for a molecular marker corresponding to lymph nodes metastases. Their results show that elevated levels of L1 cyclin expression occur in HNSCC with locoregional lymph node metastases and independently of the anatomy and T-stage of the primary tumor. They also showed that a higher level of CCNL1 gene amplification was associated with shorter survival [81]. Amplification of the CCNL1 gene in squamous cell carcinoma was also examined by [PERSON] et al., 2006 [79] In their studies, they showed a higher level of cyclin L expression in HNSCC. Cyclin L was located mainly in the nucleus of the head and neck malignant tumor cells. The authors suggest that overexpression of the CCNL1 gene can influence the splicing pattern of particular genes, and L1 cyclin itself may play a key role in RNA processing and contribute to HNSCC progression [79]. In turn, in the case of HCC cyclin L2 overexpression is observed. [PERSON] et al.